In clinical trials, we randomize to ensure the blind. But even the most secure randomization algorithms, which provide the least predictability, have a real risk of unblinding when implemented.

In a recent webinar, Calyx’s Head of Statistics and Product Support Services, Malcolm Morrissey shared his experience on how to identify the randomization implementation options that could lead to unblinding of the block size or partial unblinding of subject treatment.

Here he addresses some of the questions that arose during the webinar related to how Calyx mitigates this risk of selection bias at the site, as well as other practical issues associated with randomization, such as capping and trends in methodology.

What is Calyx’s approach to sending Data/Reports that are requested by DTRF (e.g., via email, to a safe location) or does it only lie on the requestor’s (sponsor) decision?

Calyx follows the requestor’s preference because some sponsors cannot receive password-protected files of various forms directly due to their email account settings/security/firewalls.

Calyx’s process for sharing password-protected files requires the password to be collected from our 24/7 Service Desk and only the named/approved contact can receive that password.

When using the transmission to a safe location/portal, Calyx does advise the use of a test file before posting unblinding information.

Calyx has on occasion seen the test file identify that the chosen location is not suitable for the blinding status of the data. So, we have not seen a safe location/portal remove risks of data transmission.

“Over the last 10 years, we have observed a conservative trend within the EU/US and a preference to stick with blocked randomization designs.”

– Malcolm Morrissey, Head of Statistics and Product Support Services , Calyx

How does stratifying by site impact the blind? Does it make it better or worse?

Stratifying by site will increase the risk of selection bias because the randomization records will be dedicated to a site and another site cannot take the next record in the sequence.

So, if the next entry becomes predictable, then the risk of selection bias is evident.

Mixed block sizes or alternative randomization methods will help to reduce predictability of the randomization sequence in this case.

Calyx wouldn’t typically expect to see an open-label study stratified by site for that reason.

What is Calyx’s stance on randomization caps? Specifically, treatment arm caps?

Calyx will always seek to understand the background and the specific impact on the patients, but the starting point for discussions would focus on closing all treatments in the capped group at the same time to avoid any differences or time effects. For example, if the capping was being used to control entry into a subset by each treatment, then could the IRT system stop allocating subjects to the subset when all treatments have reached their cap, such that some treatments may have over-recruited to the subset when the last treatment reaches its target.

This approach may be unethical if subjects undergo an invasive procedure as part of that subset. In this situation, we could discuss the risk of partial unblinding versus using ‘forcing’ to complete the recruitment in the subset without any treatments going over their target.

Generally speaking, in a large Phase 3 or 4 study we would normally see a sponsor prefer to avoid any manipulation of the randomization sequence through forcing.

Do you see an up-tick in usage of baseline adaptive algorithms (e.g., minimization and its extensions) to mitigate the risks associated with a rand list? Any specific blinding considerations with baseline adaptive algorithms?

Historically Calyx has seen minimization used to achieve balance in studies with many stratifying factors; this is a direct justification for using the method because a blocked randomization would not achieve the required balance, as mentioned in the ICH E9 guidance.

Over the years Calyx has seen a growing reluctance to this method due to a concern about the additional need for supporting sensitivity analysis, requested on occasion by regulators.

We understand the request is not consistent and would require extra work involved in a re-randomization test when requested.

A long time ago there was concern about minimization calculations being programmed on a study basis incurring programming errors; this is not an issue these days with pre-validated modules typically available in IRT and studies simply being parameterized within pre-validated code that provides full audit trail logging of the calculations.

Currently the increase we see in use is only within the APAC region, with many biostatisticians preferring the features of these methods over blocked randomization, which includes improving unpredictability as well as treatment balance control.

Calyx has been party to many discussions in the EU on the benefits of these methods in 2022 (with more of a focus on reducing predictability than we had seen in the past) and we expect to see an increase in the use of these methods as these discussion groups exert influence over future protocol design.

Over the last 10 years, we have observed a conservative trend within the EU/US and a preference to stick with blocked randomization until regulatory guidance forces change.

Click here to chat with one of our IRT design experts to learn how they customize an IRT solution to minimize RTSM risks to drive your trial’s success.

Supply chain experts behind Calyx IRT deliver valuable service to improve clinical trial efficiencies

Nottingham, England and Morrisville, NC – March 7, 2023 Calyx, the eClinical and Regulatory solutions and services provider relied on for solving complex data challenges in clinical research, today announced the availability of Calyx Supply Simulation, a clinical trial supply forecasting service available through Calyx’s in-house expert statistical design and trial supplies consultants.

Clinical trial sponsors can leverage the simulation service to inform decision-making related to the quantity of medication produced for use in clinical development. The service helps sponsors improve clinical trial efficiencies by evaluating the amount of medication required to start and maintain clinical trial enrolment, predicting how long an existing amount of study medication will last, and determining the optimal site and depot buffer stock quantities required to ensure dispensation while reducing the cost and burden of excessive drug wastage.

“We’re pleased to offer this valuable service so that global clinical trial sponsors can reduce the risk of drug availability impacting their clinical studies as patients progress through the dispensing events of clinical trials,” said Juan Munoz Pujol. “In addition, by optimizing supply requirements upfront with Calyx Supply Simulation, sponsors can minimize the amount of drugs that end up destroyed during clinical trials, which will reduce excessive drug wastage and help sponsors meet their corporate sustainability goals.”

Calyx’s team of expert supply chain analysts – who bring a collective 100 years of experience in Randomization and Trial Supply Management (RTSM) – work closely with each trial sponsor to understand their specific challenges and tailor the simulation to meet their unique needs. Based on sophisticated simulation modelling methodology and using over 50 design parameters that closely mimic an Interactive Response Technology (IRT) system, Calyx Supply Simulation considers multiple, real-life fixed and variable domains and the ‘what if’ scenarios that often occur during clinical trials.

Click here for more information on Calyx Supply Simulation.

About Calyx

Through innovative eClinical and Regulatory solutions and services, Calyx turns the uncertain into the reliable, helping bring new medical treatments to market reliably. With deep expertise in clinical development and 30 years supporting trial sponsors and clinical research organizations, Calyx harnesses its intelligence and experience to solve complex problems, deliver fast insights, and get new drugs to market every day.

Medical Imaging | IRT | CTMS | EDC | RIM

Take your trials further with intelligent insights at or at LinkedIn, Twitter, or Facebook.

In an earlier blog , we discussed some randomization and trial supply management (RTSM) factors sponsors should consider when planning trials for rare disease treatments. These included the variability in how many sites are required to enroll so few patients, and how to reduce drug wastage, based on the high expense of rare disease treatments.

Here we address additional challenges, including the length of rare disease trials, the role of cell and gene therapy, and how a reliable, full-service interactive response technology (IRT) system backed by trial supply experts can tackle these and other challenges to drive trial success.

Trial Length and Support Needs

When many sites are required to meet patient enrollment goals, sponsors should be prepared for very long trials. The longer the trial, the more likely it is that design, protocol, and/or packaging changes will be needed. Being able to customize your data collection processes and make changes to the way trial supplies are managed and distributed is critical.

By working with experienced RTSM professionals, study teams receive the study support they need throughout the life of their trials. With Calyx IRT, that includes access to supply chain experts who assist the trial team as changes need to be made, providing context for the IRT system design and what options are available. They work closely with our team of professional project managers who support the study throughout its duration to ensure study continuity with no impacts to drug availability and distribution.

In addition, sponsors need to be prepared to capture a significant amount of observations and data points per patient. A thorough IRT system will enable sponsors to customize their data collection and reporting as needed, regardless of how much data is captured and/or how their data needs change throughout the trial.

“In individualized therapy trials, IRT setup is impacted by the need to manage temperature limits and expiry dates for products in both frozen and thawed states.”

— Malcolm Morrissey, Head of Statistics & Product Support Services, Calyx

Individualized Therapy Trials

When a rare disease treatment is an individualized therapy, the logistics around RTSM are even more challenging. Clinical trials involving stem cell therapies present added complexity regarding treatment logistics: the treatment is collected from a patient or donor, shipped to a manufacturing site, modified, and then shipped to the treatment facility for patient administration.

Effective treatment requires cell preservation, which is often done by cryopreservation. If the cryopreservation is not well-managed or is suboptimal, cell viability and the therapy production process can be negatively impacted. Additionally, the efficacy of the therapy may be compromised due to non-ideal frozen storage conditions.1

Frozen storage conditions may be considered extraneous to the IRT by some, but functionality such as tracking of temperature limits for the product and quarantine functionality, as well as management of a different expiry date for the product in a frozen and thawed state, all impact IRT set up and supply chain management. A robust IRT solution for handling a changing expiry date following the change of storage state/condition is a critical factor and not one that is typically seen in many clinical trials with temperature sensitive medication. It is a feature that has only gained increased use in recent years.

Additionally, the timeline of events involved in the manufacturing process could require careful oversight and in some cases a degree of control. The controls applied could be used to avoid exceeding manufacturing capabilities on a given day, for example. This would depend upon the size of recruitment within the trial or the number of protocols calling on the patient-specific manufacturing at one time.

The controls in the IRT could be as simple as applying a daily limit (or cap) to a future planned visit date entered in to the IRT for a subject’s next visit. Alternatively, Calyx has designed a booking system with bespoke rules that tackles the planning of visit slots for a given site in a trial. The booking system runs an algorithm using a set hierarchy of preference criteria to assign manufacturing slots to sites for specific planned visit dates. The algorithm can include in the assignment hierarchy, preferential sites, consideration of whether the site was allocated a slot in the last algorithm run, and other client-specific criteria for slot assignment. This booking system can manage depot capabilities and place designated limits on depots, as needed, to ensure their ability to make individualized therapies throughout this form of rare disease trials.

In both scenarios, the resupply algorithm can still include patient-focused predictive supply to cover the needs of ongoing patients across the program.

The definition of supply strategies becomes more complex if protocols include both pooled medication and protocol-specific kit types, or if the sourcing strategy varies between kit types, with some medication being locally sourced, and others sourced centrally. Thanks to their extensive experience in clinical inventory management, Calyx supply management experts understand and apply the best practices that help sponsors adapt to any requirements.

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.

2022 brought many healthcare advances and opportunities for life science professionals to stay up to date 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, white papers, webinars, 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.

This blog series addresses the trigger points for unintentional unblinding, how partial unblinding can become full unblinding, and some controversial issues related to unintentional and partial unblinding in clinical trials.

In 2021, Calyx advanced its strategy of partnering with best-in-class technology providers to offer innovative imaging biomarkers required to find new treatments for unmet medical needs. Our groundbreaking partnership with Qynapse enables our clients to more confidently assess the full potential of treatments in development for Multiple Sclerosis, Parkinson’s, Alzheimer’s, and Huntington’s disease, as well as other neurodegenerative disorders. And our partnership with Neosoma delivers novel, improved AI-based neuro-oncology imaging assessment to clinical trial sponsors developing new treatments for gliobastoma and other life-threatening neuro-oncological diseases.

The Journal for ImmunoTherapy of Cancer recently published ‘Comparison of tumor assessments using RECIST 1.1 and irRECIST, and association with overall survival,’ marking the first time immune-related criteria show correlation with Overall Survival as its most meaningful endpoint in the treatment of cancer patients.

The publication demonstrates the benefit to a subgroup of patients who otherwise would have foregone treatment and survival benefit when relying solely on RECIST 1.1 instead of irRECIST, as irRECIST takes the entire tumor burden including new tumor growth into consideration.

In this webinar, co-authors Peter Eggleton of Merck and Oliver Bohnsack of Calyx – leading experts on RECIST and irRECIST – discuss the implications of these findings, what it means for oncology clinical development and treatment decision-making, and why irRECIST easily can and shall replace outdated RECIST 1.1 on all solid tumor trials going forward.

In rare disease trials, it is critical that trial supplies are available when patients are identified, and that drug overage is minimized – a real challenge due to larger numbers of investigative sites typically required to meet trial enrollment levels. Which is why we’re honored that so many sponsors of orphan drug-designated trials have entrusted their RTSM needs to Calyx IRT and continue to rely on our expertise as they bring safe and effective treatments to patients in critical need.  Learn more about Calyx IRT.

This blog series reviews the factors regulatory affairs professionals should consider as they prepare for eCTD 4.0 implementation, beginning with people and business processes, the impacts of new concepts and terminologies, and the challenges to be expected.

What are the consequences of deferring IRT functionality to meet clinical trial start dates? In this Applied Clinical Trials article, Calyx’s Craig Mooney reviews the inefficiencies and potential quality / regulatory risks likely to occur.

At Calyx, we have a long history as part of a CRO, so we know how a CRO functions, the challenges you’re up against, and the importance of keeping your customers satisfied. This inside knowledge affects every aspect of our CRO relationships and makes us more efficient and easier to work with.

Our Activate Solutions for CRO Partners Program enables CROs of all shapes and sizes to partner with Calyx and extend our advanced technology and proven services to drive success for their customers. In 2022 we added more CROs to the program – get to know some of them and learn how they’re partnering with Calyx to deliver more value.

80 sites enrolling 150 patients: How do you minimize overage without burdening your supply team? Learn how one of Calyx IRT’s advanced trial management options solved the complex in this case study.

In this episode of the Calyx Café, Patient Advocate Emily Epstein discusses the importance of supporting clinical trial patients’ mental health and the impact that clinical trial technologies – including DCTs – may have on patient welfare.

Your clinical trials deserve every chance to succeed. And your monitors deserve the most effective tools to improve trial efficiencies. This brochure describes why Calyx CTMS is the solution.

Calyx advanced inventory management strategies can reduce clinical trial drug wastage by up to 50%

Nottingham, England and Morrisville, NC – November 22, 2022 Calyx, the eClinical and Regulatory solutions and services provider relied on for solving complex data challenges in clinical research, announced today that a Top 10 pharmaceutical company is leveraging medication pooling, an advanced inventory management strategy available through Calyx IRT (interactive response technology), to improve drug distribution efficiencies and reduce drug wastage in an ongoing, global clinical development program.

The Top 10 pharma company is benefitting from Calyx’s proven solution which supports medication pooling and just-in-time labelling across multiple studies in their program. Calyx IRT medication pooling enables study drug to be shared across multiple protocols, enabling trial sponsors to reduce the impact of excessive drug wastage typically incurred during drug development.

“In addition to reducing drug wastage, medication pooling delivers an effective solution for addressing scarcity concerns and other restrictions which affect the supply of medication during clinical trials,” said Malcolm Morrissey, Head of Statistical Design and Trial Supplies at Calyx.

Medication pooling is possible when a suite of studies or programs use the same medication. The Top 10 pharma company implemented IRT medication pooling for a suite of five studies involving nearly 500 sites using 20 depots across 30 countries. In the first year of the program, Calyx has managed 1.5 million packs of a dozen medication types.

This latest innovation around pooled medication has already been deployed in 80 trials to date across North America, Europe, and Asia. IRT medication pooling is one of Calyx’s many advanced inventory management strategies that could help trial sponsors reduce drug wastage by up to 50%.

Click here for more information on how Calyx IRT self-service tools and other advanced functionality drives clinical trial success.

About Calyx

Through innovative eClinical and Regulatory solutions and services, Calyx turns the uncertain into the reliable, helping bring new medical treatments to market reliably. With deep expertise in clinical development and 30 years supporting trial sponsors and clinical research organizations, Calyx harnesses its intelligence and experience to solve complex problems, deliver fast insights, and get new drugs to market every day.

Medical Imaging | IRT | CTMS | EDC | RIM

Take your trials further with intelligent insights at or at LinkedIn, Twitter, or Facebook.


Christine Tobin | [email protected] | +1 412-628-8598

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