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BACKGROUND

A leading pharmaceutical company selected Calyx IRT to provide randomization and trial supply management (RTSM) services for two Phase III, multi-country studies. During trial execution, a safety regulation was issued that required the company to modify its primary packaging due to safety risk concerns for some patients.

This unexpected study change was complicated in that it only affected sites in a single country and each trial had at least 12 countries participating.

At the time, the inventory was already in use across all sites and all countries, with several hundred patients enrolled and randomized, and the trials were barely at the halfway mark.

The client came to our team with a date when the new inventory needed to start being dispensed for patient visits based on the regulatory requirements. So, the experts behind Calyx IRT went to work.

Case Study
The Value of IRT Expertise and Flexibility: Managing Unexpected Study Challenges

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CHALLENGE

This situation presented several unique challenges in that, for the study to continue as planned, the sponsor had to ensure new inventory could be shipped to the sites in advance of, but not dispensed to patients until the transition date. This meant the sponsor must:

  • Enable sites to continue dispensing current inventory in its original form up until the required date of transition
  • Produce and ship the new inventory so that sites would have it available to dispense when ready
  • Ensure, at the time of transition, all the old inventory was removed from the impacted sites
KEY HIGHLIGHTS
IN CLINICAL TRIALS, NOTHING GOES ACCORDING TO PLAN.

In this case:

  • Safety regulation issued mid-way through two Phase 3 trials
  • The change only affected one country
  • Each of the sponsor’s trials involved 12 countries
  • New inventory had to be shipped to affected sites before the changeover date
  • New inventory couldn’t be dispensed until after the changeover date
  • Old inventory had to be collected and destroyed
  • The system allowed the sponsor to determine when they were ready for their depots to ship new inventory
  • Calyx enabled the sponsor to remain compliant and continue their trials with no disruption to patient visits

Rely on Calyx IRT to tackle all your unexpected study challenges

SOLUTION

Calyx gathered a team of internal experts to discuss the best approach for this transition. This team included the study’s project manager –
who understood the sponsor’s IRT standards – a solutions designer, validation engineers, customer service representatives, and our statistical design and trial supply consultants.

Together, the team reviewed the study team’s needs and discussed the options to accommodate this new regulatory requirement. The goal was to build a structured transition plan to ensure on-time compliance with the new requirement.

The resulting solution was multi-phase:

  • While the sponsor was packaging the new inventory, Calyx planned the updates to country- and batch-level inventory management settings. Calyx IRT provided intricate control over what was being shipped to which countries and when, including the prioritization of batches.
  • This transpired while the existing IRT system also continued shipping and dispensing only the current inventory for patient resupply needs.
  • Shipping the new inventory was one part of the challenge. Once the new inventory arrived on site, Calyx had to complete the transition in line with the sponsor’s date requirement without impacting patient visits.
  • When the transition date arrived, the Calyx team coordinated removing the old inventory from site stock. The system also ensured the country settings were all automatically set so future shipping and dispensation only included the new inventory.

RESULT

The sponsor was delighted with Calyx’s commitment to finding a solution and the flexibility built into Calyx’s IRT system that enabled them to meet their trials’ changing RTSM needs. Even though the deadline date was postponed, because the Calyx solution was flexible and future-proof, the change-over occurred without any problems. Patient enrollment continued, dispensation visits occurred, the original inventory was destroyed, and the company met the deadline, keeping them compliant with this important regulatory change.

Contact hello@calyx.ai to learn how Calyx IRT can help your clinical trial succeed.

Situation

Calyx IRT was the system of choice for a study involving patients admitted in intensive care units (ICU) due to complications linked to COVID-19 infection. The study was run through a CRO, and Calyx worked directly with both the CRO and the sponsor team.

On paper, the study was a relatively simple IRT design, investigating whether the study drug would reduce the time spent in ICU. Patients were enrolled in the study upon admission, treated in the ICU, and dosed up to 6 times over the course of 28 days or until discharge, whichever was earliest. There was an established depot network from the study start and supplies to sites were based on expected recruitment rates.

However, clinical trials rarely go to plan, do they?!

Challenge

During trial execution, the sponsor had to switch distribution vendors, as they were not satisfied with the one selected initially. The switch had to be done in flight, while sites were still recruiting, without impacting supplies to sites and patient recruitment.

For the last 10 months of the study, the sponsor faced a critical situation regarding medication management. Due to a longer start up period than initially expected the medication in stock at depots and sites was about to reach expiry limits. Without any additional stock and no time to manufacture more medication, they risked not being able to supply patients with medication, which would have resulted in the trial closing before reaching the required sample size.

Solution

The Calyx project manager leveraged their experience managing similar situations to address the challenges the sponsor faced.

Switching Distribution Vendor

Calyx IRT includes standard integrations for both distribution vendors that were used in this study. Switching vendors mid-study required changing the depot network, as well as applying different integration standards, to support ease of use for the new distribution vendor.

Thankfully, Calyx IRT inventory management includes flexible settings made to deal with unforeseen situations like this one. We used those settings to increase the stock of medication at sites, anticipating that stocks would need to last longer during the depot transition period.
We supported the clinical supplies team with transferring medication to the new depots and releasing the medication for use once it was confirmed to be available at the new depots. The depot transition and new integration were invisible for sites.

The Calyx project manager was instrumental in advising the CRO and sponsor how to navigate this situation, recommending the most suitable options available. They coordinated the various updates required and released them all at the right time, in alignment with the physical move of the medication stock.

Using Medication Close to Expiry

Situations where medication is reaching expiry dates are tricky. Calyx IRT inventory management includes flexible Do Not Ship and Do Not Dispense settings, which can be amended down to patient dispensing level if required. We would usually recommend not amending those settings, but our team has the right level of expertise to implement those updates safely.

For this study, the Calyx project manager worked closely with the clinical operations team whenever a patient needed medication. This included actions to ensure that patient status within the IRT were proactively updated to reduce the risk of predicting too much medication, therefore increasing accuracy of shipments. They demonstrated excellent communication and prioritization, ensuring inventory management settings were amended immediately and appropriately to allow medication dispensing to patients. The Calyx project manager kept the study team informed throughout the process, allowing the team to set expectations with monitoring and site staff.

Result

Thanks to Calyx’s flexible technology and excellent project management, the sponsor was able to recruit the number of patients they needed and dispense medication to those patients without putting their safety, or the trial, at risk.

The trial was a success and supported the sponsor’s request for Emergency Use Authorization from the FDA for the treatment of critically ill COVID-19 patients.

Case Study

Calyx IRT: Ensuring Trial Supply through Unexpected Study Changes

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Situation

LG Chem was looking to outsource two trials, one of which had a complex randomization design: the randomization ratio was 10:10:10:10:1 and it included three stratification factors. Some strata targets were relatively low, increasing the risk of not fulfilling the allocation ratio within each possible stratum level. In addition, the protocol design stated that at month six, subjects randomized to the placebo arm would stop treatment and be considered as having completed the study.

Overview

A typical randomization design using a blocked list would require a very large block size of 41, which was not appropriate, considering the low recruitment target for some strata. Although a list could be built to meet those requirements, the sample size was not large enough to fill a block for each stratum, which would inevitably result in an imbalance of the allocation ratio at the end of the trial.
LG Chem was was also concerned that the population in a stratum may be too low to include all treatment arms. Without the right randomization design, LG Chem might need to increase recruitment targets, subsequently increasing study timelines and budget.

An additional challenge was the potential partial unblinding of the subjects within the same block as a placebo subject who reaches month six.

Solution

One of Calyx’s randomization experts was engaged in discussions with LG Chem during the IRT vendor selection process and throughout the study setup phase. They shared their point of view from a biostatistical aspect, and challenged the randomization design to confirm what could and could not be achieved through a blocked list.

They concluded that the risk of imbalance was too high to use a typical blocked list randomization approach and discussed the concept of minimization with LG Chem.

To highlight the relevance of a minimization design, they ran a simulation through a proprietary SAS program, which provided an idea of the balance across treatment arms and strata. The simulation was used to demonstrate the impact of various minimization algorithm parameters, helping the study team select the right settings in IRT.

For example, when using a dynamic randomization method such as minimization, the ICH-e9 advises that a random element is used within the process to make it non-deterministic. The size of the random element was investigated through simulation, along with the usual stratum weights, for the given populational characteristics of stratum recruitment. The random element is a powerful tool to reduce the predictability of assignment but can also affect the allocation ratio achievable with a small recruiting stratum group.

The simulation exercise provided a useful visualization of how minimization parameters would impact the study outcome, giving the LG Chem team confidence that the IRT randomization design would be suitable. The Calyx project team used Calyx’s own pre-validated parameterized minimization module for the ‘Pocock and Simon Method of Minimization with Biased Coin Assignment,’ which reduces the risk usually associated with ‘bespoke programming’ of such complex randomization methods. The module includes a full audit trail of each randomization event, allowing one to review why a patient was assigned to a specific treatment arm, and what calculations were done by the system.

Resolution

The LG Chem study team trusted Calyx to meet the protocol’s complex randomization design, with adequate settings that ensured the right balance between treatment arms. Calyx’s expertise was a key component to the success of the trial setup.

“We relied heavily on Calyx’s IRT expertise and followed their recommendations for overcoming our studies’ challenges, resulting in a solution that perfectly met our RTSM needs for two complex gout trials.”

Book a meeting with Calyx randomization experts to learn more about minimization and other advanced RTSM algorithms to drive your trial’s success.

Case Study

LG Chem Randomization Challenge Resolved by Calyx IRT

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Situation

  • Phase III multi-center, double-blind, randomized, placebo-controlled study
  • 150 patients
  • 80+ sites across 25 countries

Challenge

The sponsor was concerned that the following factors would cause a very high level of drug wastage:

  • Large number of sites
  • Clinical supplies team did not have the capacity to closely monitor sites

Case Study

Reducing Overage with Calyx IRT: Minimize Monitoring Burden while Optimizing Supplies

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Solution:

Calyx supply chain experts recommended Calyx IRT’s automated supply strategy management to:

  • Ensure each site is appropriately stocked by changing the IMP supply levels to match current recruitment rate
  • Take the burden off the clinical supplies manager
  • Minimize drug wastage
Identify which sites are active
Assess the site based on defined parameters
Switch the supply strategy, if needed
Generate shipment specific to the site’s needs

What is a supply strategy?

Supply strategies determine what stock is sent to a site; they combine site needs for both:

Buffer:

  • for randomization & for unplanned needs, for example, replacing damaged stock
  • quantities based on assumptions made at the start of the trial

Prediction:

  • typically, for subjects from randomization onwards
  • quantities based on subject treatment group, dosing regimen & visit schedule

Typical IRT approach

When the site is first activated, a strategy is selected based on the expected recruitment rate; this can be changed by the clinical supply manager via the IRT whenever the actual recruitment rate differs, so requires active monitoring

Advanced IRT approach

Automated supply strategy management differs as a site’s strategy is automatically changed to align with its actual recruitment rate.

The automated supply strategy management process:

For this study, Calyx IRT ensured that all subjects currently in screening could be randomized (and for this design received 1 kit of active or placebo).

The stock in the initial shipment was based on a dynamic count of subjects actively in screening at the site

The stock in the resupply shipments was based on a dynamic count of subjects actively in screening at the site

The quantities to ship per strategy were defined based on assumptions at the start of the trial with the support of the study’s dedicated Calyx IRT randomization and trial supply expert.  Clinical Supply Managers were able to amend those quantities through Calyx IRT self-service tools, once real-world patient and site data was available.

The Calyx IRT design also included:

  • The option for the clinical supplies team to easily override the automated supply strategy switch via our inventory management web system
  • Country-specific opt-outs for the automated process
  • Specific supply strategies for locations with a long lead time for shipments

Result:

By using Calyx IRT to automatically optimize the supply strategy for the site’s current recruitment situation, the sponsor was able to:

  • Relieve the clinical supply manager’s burden of closely monitoring each site’s supply levels against patient recruitment
  • Avoid failed patient visits due to insufficient medication
  • Ensure that each site is on the optimum supply strategy for their current recruitment rate
  • Keep drug wastage to a minimum

More on automated supply strategy management

Automated Supply Strategy Management is one of Calyx IRT’s advanced trial supply management options; it’s a flexible approach that can be tailored to specific protocol requirements and supply criteria.

The approach can be helpful for any type of study but is particularly useful at reducing the burden on the clinical supply manager when there are many sites.

Trials which benefit most

Large trials with many sites

Trials with a combination of local and central sourcing of IMP

  • The greater number of IMP types, the larger the possible combinations for resupply strategies
  • Automated switching would be used to assign a strategy based on the source settings for a site

Comparator trials where the comparator is known to be different based on patient characteristics

  • Automated switching could be used to monitor the level of comparator medication based on the number of patients with the required characteristic

Calyx RTSM expertise

Our dedicated IRT randomization and trial supply experts are here to help with any questions related to advanced trial supply management.

If you are interested in using automated supply strategy management, Calyx RTSM experts can assess the suitability of the method for your design considering:

  • Number of sites
  • Recruitment rates
  • Supply of future visits
  • Medication costs
  • Medication availability

Contact hello@calyx.ai to learn how Calyx IRT and our dedicated supply chain experts can design an IRT system to drive your trial’s success.

Situation

  • Phase III study evaluating the efficacy of 2 different doses of active drug compared with placebo
  • 500 patients
  • 80+ sites participating across six countries
  • Site stratification

Challenge

  • IMP was very expensive, so ensuring patient supply while limiting overage was critical
  • Storage of medication was limited for many sites

Case Study

Optimizing Supplies with Calyx IRT: Ensure Patient Supply while Limiting Buffer

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Solution:

  • Calyx RTSM experts recommended “randomization prediction,” one of our advanced trial supply management options; this sends only the exact medication a site will use for upcoming patient randomization
  • Traditional IRT solutions base site stock levels on the expected number of randomizations and the amount of medication used for each treatment group
  • With randomization prediction, Calyx IRT sends medication to each site based on upcoming treatment group assignments known from the randomization list
  • Calyx RTSM experts worked with the sponsor to understand the expected site recruitment rates and recommended a range of supply strategies including low, medium, and high recruiter

We determined how many randomization list records’ worth of medication would be covered per supply strategy

Result

  • Randomization prediction ensured a reduction in overage by removing the buffer
  • The stock required to be shipped to the site was reduced, as shipments contained specific medication for randomization assignments
  • Patients had the right drug at the right time

Randomization Prediction

Randomization prediction is one of Calyx IRT’s advanced trial supply management options; a flexible approach that can be tailored to specific protocol requirements & supply criteria.

If your study stratifies by site, Calyx IRT can send IMP to each site specific to upcoming treatment group assignments; this ensures overage is reduced.

Additional Features

— Can also cover medication needs for the next visit; beneficial if the next dosing visit is close to randomization

— Can be used with another stratification factor, in addition to site

— Does not require sites to have all types of medication for a randomization to proceed

— Can be combined with standard buffer & prediction strategies

  • Covering subsequent visits
  • Including buffer stock in case of IMP damage

Calyx RTSM Expertise

Our dedicated IRT randomization & trial supply experts are here to help with any questions related to advanced trial supply management.

If you are interested in using randomization prediction, Calyx RTSM experts can assess the suitability of the method for your design considering:

  • Recruitment rates
  • Supply of future visits
  • Blinding considerations
  • Randomization and statistical considerations

Contact hello@calyx.ai to learn how Calyx’s expertise in IRT can ensure your trials’ success.

Situation

A leading biotechnology company transforming their business across multiple therapeutic areas came to Calyx for help in designing an IRT system to overcome numerous obstacles:

  • Some compounds were owned jointly with other companies, requiring more flexibility and adaptability in their IRT designs
  • Delayed protocol feedback from regulatory agencies increased pressure on study timelines
  • Rapidly expanding pipeline resulted in increased IRT deployment demand in support of more trials
  • Already strained resources were expected to roll out studies faster and in parallel to keep up with the portfolio growth
  • Other system-wide impact items included protocol amendments, regulatory reporting, and response capability
  • Increased demand for more trials taxed their internal resourcing and capacity

Case Study

Increase Efficiencies through Effective IRT Partnering 

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Challenges

Calyx was asked to come up with a solution that would alleviate the RTSM-related pressures on the study team, freeing them to focus on other critical development needs. The challenges put forward for the RTSM technology were:

  • Create repeatability in the design and delivery of the Interactive Response Technology (IRT)
  • Streamline processes such as communication channels and study requirements documentation
  • Create efficiencies for sites and in the delivery of each study’s IRT implementation
  • Quickly implement protocol amendments to address the lag time of regulatory response

The expectation was that when these key areas were addressed, the biotechnology company would have the agility and flexibility needed to conduct their trials with confidence, ensuring continued support and growth of their portfolio. Naturally, this had to be accomplished without introducing risk or loss of data quality and accuracy.

Additional expected outcomes included the ability to:

  • Ensure true alignment between IRT delivery and study teams
  • Increase access and visibility into patient and supply chain data
  • Leverage automation as part of the solution
  • Increase efficiency in end-to-end IRT delivery

Reduce if not eliminate:

  • Time needed to gather, document, and review requirements
  • Need for custom programming
  • Time required for User Acceptance Testing

Solution

The IRT system Calyx implemented was a business solution, encompassing both technology and service and ensuring that the people, technology, and processes were agreed upon by both organizations. The technology part of the solution included the development of IRT standards as well as the supporting business processes. It also required some processes to be adapted or new ones created.

Standards

Developing IRT standards was a collaborative process, which ensured the standards covered the three typical levels of functionalities in the IRT system:

  • Core standards
  • Sponsor standards
  • Protocol requirements

Typical functionalities of Calyx’s core IRT standards address such items as randomization algorithms, inventory management functionalities and algorithms, drug accountability workflows, and integrations. As a result, Calyx standards come with inherent system flexibility and adaptability to align each IRT deployment to the study protocol without the need for custom programming.

Sponsor-level standards encompassed their commonly used functionalities or settings, such as countries, depots, and inventory management preferences, all linked to their existing processes.

Process-related items included how project communication or standards adaptation would be handled, the communication channel, forms, templates, and other standard documentation such as project agreements, unblinding addendums, and project requirements form. They also included site-level processes identifying how site users were to interact with and utilize the system. This drove some of the biotechnology company’s specific user access requirements and standards development through reporting accessibility and useability.

Partnerships

As part of the solution, both organizations formed a partnership which included aligning the Calyx IRT delivery team with the client’s study team by therapeutic area. Portfolio directors, solution designers, engineers, validation, and support personnel, along with commercial business development and solution consultants were aligned as part of the partnership.

Portfolio and business development directors attended monthly governance meetings where the pipeline was reviewed, and high-level planning and agreements were made from a pipeline support perspective. Additionally, discussions included any items that may have had an impact on the solution such as standards enhancements or changes required to align the standards to business changes or to simply drive new requirements.

Benefits

  • Increased efficiency in design, delivery, and communication, while reducing risk and providing the visibility and traceability requested
  • The sponsor engages with the same IRT delivery teams across multiple trials, building trust and mutual understanding
  • Increased site and staff efficiencies provide the ability to support sustained growth
  • Increased data quality and consistency through standards and automation

Results

  • Sponsor realized the value and benefits of program management
  • Therapeutic area team alignment means studies are delivered by same team over and over
  • Ability to adapt to un-expected life altering events: COVID Program successfully supported with 10 study go-lives in record setting deployment timelines
  • Demonstration of how program management approach combined with client standards and processes through a true partnership increases efficiencies and sets all up for future successes

One of the truly measurable results of the combined standards and partnership solution is the enhanced efficiency and adaptability the biotechnology company experienced while responding to the COVID-19 pandemic. Based on a solid partnership between the therapeutically aligned Calyx IRT team and the COVID-19 study team, the IRT system was delivered within six days, freeing the sponsor’s subject matter experts to focus their efforts on solving issues linked to the effect of COVID-19 on other ongoing trials.

The biotechnology company was granted emergency authorization of its compound and was able to make one of the first COVID-19 treatments available to patients and first responders. Since the pandemic started, the biotechnology company has deployed ten COVID-19 studies of potential COVID-19 treatments, all initiated within similar expedited timelines.

The sponsor knew exactly what could be achieved with this very important program. Thanks to a strong partnership built over the years, they knew they could trust Calyx to deploy their program of COVID-19 studies accurately and in record time.

Key Highlights

  • Ability to support any type of randomization
  • Statistical designers with average 7+ years’ experience in IRT and 250+ adaptive trial designs delivered
  • Secure data blinding, resulting in safe navigation through Calyx IRT and safe communication with our helpdesk
  • As little as 4 weeks from requirements approval to UAT
  • Integrations with eClinical suites (EDC, ePRO, central labs, supply management, etc.); Calyx IRT successfully exchanges more than 10,000 files with other systems daily
  • IRT-dedicated helpdesk, specialized in managing the challenges of patient and inventory management for your sites and trial teams
  • IRT self-service tools allow you to quickly adapt to varying site recruitment levels, change/add supply strategies, and activate new countries and depots

Used in over 4,500 global clinical trials, Calyx IRT takes the worry out of randomization and supply management – so you can concentrate on study success.

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