Beyond the audit: Taking quality and compliance to new heights with your IRT
By Matt Lowrie
Quality Assurance and Regulatory Compliance Manager
The IRT in your clinical Trial
IRT lives at the center of the eClinical world. It is often one of, if not, the first captures of subject screening, randomisation assignment, stratification, and drug dispensation. The IRT has become far more complex and involved than it was 20-30 years ago.
It is critical that the IRT is on the critical path for the trial, it is also critical that the IRT remains in alignment with the Clinical Trial Protocol. It’s best to remember those two key items when building the system. The IRT often interacts with other eClinical systems, which means the data flow should be looked at and it’s important to consider these facts and how you will maintain adherence to the various regulations not just during the trial, but during inspections and data reconciliations.
Selection and Design of the IRT
Given the expense of a clinical trial, and the spend for an IRT, getting the wrong one could destroy the total investment. To help you determine what and where you should be looking, there are several factors that need to be assessed. Part of that assessment is an audit; however, you should be creating a relationship that is ongoing and not supported by an every two-year visit.
Step 1 really should be the Vendor Selection. This is a fantastic opportunity to get yourself a demo of the system. Even if you have used it before, see what is new and what the system can offer you up front and out of the box. This is a chance to see if you can use what already exists to decrease costs, speed up timelines, and simplify your IRT.
Once completed I encourage everyone to open the dialogue with the IRT vendor across the stakeholders. This should absolutely include Quality and not just for scheduling a prequalification audit. The conversations should start around performance indicators, applicable documentation, support, and the best way to partner and maintain oversight of the IRT (or any eClinical system!). When we work with our partners, we make it clear- they are not alone in the trial. We are absolutely here to help and support along the way.
It is also important to create your Subject Matter (SME) team: who will provide input and approval to the UAT strategy document and UAT test scripts? Who will help execute the scripts? What design enhancements or changes are dealbreakers to closing the UAT Phase? Who needs to give final approval to move the system Live?
All of this before the system is ready to go live.
Support and Engagement
Once your study is live, it is imperative to maintain oversight on the trial. This may include regular data reviews, weekly meetings, or monitoring of the overall relationship. There are plenty of areas to consider, and luckily, you have a partner who does this across a large swath of other clients. Utilize their expertise and experience. I often see this made into something that is over complicated and resource heavy. It doesn’t need to be, the right people on the right topics can make this seamless and help fulfill your regulatory obligations regarding vendor/sponsor oversight.
It’s more than just a couple of meetings. There are aspects that should be considered such as the availability for day-to-day support, developers, and how the IRT will be supported during an inspection. This is where having a relationship that is open, and honest really helps the overall Quality and compliance of the system. Having a partner who is willing to share ideas and best practices is crucial for smooth and efficient trials.
At Almac, we support several inspections each month. The most successful of those are with our partners that we have a quick strategy meeting (30 minutes) to organize, understand scope, storyboard, and ensure all the necessary documentation and data is at the ready before the inspection even begins. Those 30 minutes save days, if not weeks, of churn, CAPAs, and updates to resolve findings.
The key principle overall is to realize it is indeed a partnership and a relationship. It needs to be treated as such with everyone involved utilizing their strengths and their partners’ strengths.
Final Thoughts
There are plenty of opportunities to demonstrate oversight, however, as an industry we need to move away from the outdated method of simply performing an audit. Audits are great as a verification, they are fantastic to help assess compliance and process, however, they cannot be used as the sole mechanism for oversight. You have a partner for your IRT who is an expert, utilize them. Ask them what they see as best practices, listen to their opinions on system design, ask about where they see potential risks or failures, and lean on them to identify how to best approach topics like User Acceptance Testing. Most importantly partner together.
Complex Innovative Designs are emerging within many clinical trial protocols. These designs often require adaptations and flexibility for the randomisation, similar to Adaptive Designs. Before entering the world of Complex Innovative Designs, it is important to understand the basic concepts of Adaptive Designs and how they may impact randomisation.
What are Adaptive Designs?
An Adaptive Design allows for a trial to adapt mid-study. These adaptations are planned and specified in the study’s protocol. The FDA defines adaptive designs as “a clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial” in their 2019 guidance document Adaptive Designs for Clinical Trials of Drugs and Biologics.
What are Common Adaptations that Impact Randomisation?
Common adaptations that impact randomisation include:
Introducing new treatments
Dropping existing treatments
Pausing and restarting treatments
Adjusting treatment allocation ratios or assignment probabilities
Sample size readjustment
How is Randomisation different from a Traditional Design compared to an Adaptive Design?
In a traditional randomisation design, the included treatments and allocation ratio are usually the same for the entire study. For instance, subjects are randomized to one of two treatments in an equal allocation ratio (1:1). One randomisation list is generated and used for subject randomisation across the study’s duration.
Whereas in an Adaptive Design, the randomisation design may change depending on the planned adaptations. For example, a study starts with three treatment groups assigned in a 1:1:1 ratio. Then based on the results of an interim analysis, one of those treatments could be dropped or a fourth treatment could be added. Therefore, the randomisation could change to either assigning in a 1:1 ratio or a 1:1:1:1 ratio. One randomisation list that is fixed with three treatments in a 1:1:1 ratio would not support the possible adaptations. Additional randomisation lists or some type of flexible randomisation would be needed.
What are Complex Innovative Designs?
Complex Innovative Designs are similar to standard Adaptive Designs, but typically include additional layers of complexity. Complex Innovative Designs have benefits such as increased flexibility and efficiency in drug development, the ability to share control arms, central electronic data capture systems and patient centricity. They are usually able to identify treatments that are effective and ineffective quicker than traditional trials.
Complex Innovative Designs include (but not limited to):
Master Protocols (Basket, Umbrella, Platform)
Biomarker-Targeted Treatments
Bayesian Response Adaptive Randomisation
Complex Dose Ranging / Dose Finding Cohorts
How do Complex Innovative Designs impact the Trial’s Randomisation?
Complex Innovative Designs that include randomisation adaptations are similar to standard Adaptive Designs, with additional dimensions of complexity. Think of standard Adaptive Designs as one dimensional where the same adaptations are applied to the entire study. If a treatment were dropped, it would be excluded from the study’s randomisation list. Whereas Master Protocols are studies that have multiple dimensions such as different subgroups, sub-protocols, sub-studies, etc. In this Complex Innovative Design case, a treatment may be dropped in one subgroup’s randomisation list, and in another subgroup, a treatment may be added. The adaptations need to be managed independently for each dimension’s (subgroup) randomisation.
Another example is the case of biomarker-targeted treatments, where only subjects who are biomarker-positive are eligible for that biomarker-targeted treatment, and those who do not have the biomarker are ineligible. Here, there is varying eligibility based on the included treatments that may or may not target specific biomarkers. The varying eligibility needs to be managed to allow or not allow assignment based on biomarker-targeted treatments and biomarker presence.
Due to the complexity involved, the implementation and management of randomisation for these types of designs often require a sophisticated Interactive Response Technology (IRT) system.
What is Successful Implementation for Randomisation of Complex Innovative Designs?
Successful implementation of Randomisation is all about being able to execute the adaptations with minimal disruptions since a key characteristic of Complex Innovative Designs is efficiency in drug development. Take the case of a study implementing a single randomisation list with the initial study parameters (e.g., included treatments / ratio) without accounting for any possible adaptations. With this set-up, if a new treatment is introduced, then a new randomisation list needs to be created and imported into the IRT system. While this approach works, it is disruptive since it incurs time and effort. A more efficient approach would be if the IRT included a flexible randomisation scheme with user ability to enter in the adaptations in real-time without having to create a new list.
What is the Optimal Level of Flexibility for a Complex Innovative Design’s Randomisation?
Every study is different, which means that each study’s optimal level of flexibility also differs. Planned adaptations are specified within the study’s protocol. Some protocols may explicitly detail the adaptations (e.g., which treatments could be added, which treatments could be dropped), while others may not. For example, a protocol states that new treatments can be introduced throughout the study’s duration as they are discovered. Since they are yet to be discovered, they cannot be explicitly specified in the initial protocol and will be included in an amendment once identified. If new treatments are expected, but not yet identified, the IRT randomisation could be built as flexible to allow new treatments to enter into the scheme dynamically through a user interface. If the protocol specifies that the ratio(s) can be adjusted, that should be incorporated into the IRT’s randomisation as well.
What is Recommended to Achieve the Optimal Level of Flexibility for a Complex Innovative Design’s Randomisation?
To be able to achieve the optimal level of flexibility, it is recommended to begin discussions on randomisation implementation early in the planning phase of the protocol. These discussions should include the key stakeholders such as the study’s clinical operations leaders, program managers, biostatisticians, clinical supply managers, along with the relevant vendor partner roles such as IRT’s biostatisticians, project managers, design, and programming experts. It is equally important to choose an IRT vendor that has the experience and expertise in implementing these complex innovative designs to be effective consultants and partners rather than simply order-takers.
Almac Clinical Technologies has the attributes necessary to successfully implement flexible randomisation for Complex Innovative Designs. Almac has a Biostatistics team that is 100% focused on IRT randomisation, and an Adaptive Design Center of Excellence comprised of cross-functional (development, testing, QA, design, project/program management) expertise to ensure every area is considered in achieving the optimal level of flexibility.
Clinical Technologies Client Design Solutions Lead
Dan Ward
Clinical Technologies PA Product Manager
What is Drug Pooling?
Effective supply management and accurate reporting are vital components of successful clinical trials. In the Interactive Response Technology (IRT) domain, drug pooling has emerged as a valuable technique for optimising logistics and enhancing data visibility. By consolidating drug supplies and providing comprehensive reporting capabilities, drug pooling streamlines supply management and facilitates monitoring of shipment and depot activities. In this blog post, we will explore the practical benefits of drug pooling in the IRT world, focusing on supply management and reporting from the perspective of supply managers.
How does Drug Pooling Help Supply Management be More Efficient?
In the context of IRT, drug pooling offers supply managers several advantages in managing clinical trial supplies. Here’s how it works:
Centralised Inventory Management: Drug pooling establishes a centralised inventory where all study drugs are stored. This eliminates the need for separate inventories for each study in a programme, simplifying supply management.
Comprehensive Supply Visibility: The IRT system provides supply managers with a holistic view of drug allocation and utilisation across multiple studies within the programme. This visibility allows for optimised planning and distribution of pooled supplies.
Real-time Shipment Monitoring: Supply managers can monitor the movement of drug supplies in real-time, tracking shipments from the central pool of depots to individual studies and their sites. This helps ensure timely delivery and enables proactive management of any shipment issues or delays.
Depot Activity Tracking: The IRT system captures and records depot activities, providing supply managers with detailed information on inventory levels, drug movements, and storage conditions. This data enables effective inventory management and ensures adherence to regulatory and quality standards.
What are the Benefits of Drug Pooling in Supply Management?
Drug pooling in the IRT world offers notable advantages for supply managers:
Streamlined Logistics: Centralising drug supplies simplifies logistics by eliminating the need for multiple inventories. Supply managers can efficiently allocate and distribute pooled supplies based on study requirements, reducing administrative burdens, and optimising the supply chain.
Enhanced Resource Utilisation: By pooling drugs, supply managers can optimise procurement and inventory management, reducing costs associated with excess or underutilised supplies. This improves resource allocation and maximises the efficiency of clinical trial operations.
Improved Shipment Visibility: Real-time monitoring of shipments allows supply managers to proactively address any issues that may arise during transportation. This ensures the timely delivery of study drugs to the intended sites, minimising disruptions and maintaining the continuity of trials.
Accurate Depot Activity Monitoring: Tracking depot activities provides supply managers with insights into inventory levels, drug movements, and storage conditions. This enables proactive management of stock levels, identification of potential bottlenecks, and ensures compliance with regulatory requirements.
How Does an IRT Impact Data Reporting and Insights?
In addition to supply management, the IRT system supports comprehensive data reporting for supply managers:
Study-specific Allocation: Supply managers can access detailed reports that indicate which study within the programme each drug shipment is allocated to. This enables accurate tracking of drug distribution and ensures that supplies are appropriately allocated to meet the needs of individual studies.
Shipment and Delivery Reports: The IRT system generates reports on shipment activities, providing information on delivery timelines, transit times, and any deviations from the expected schedule. This helps supply managers monitor and evaluate the efficiency of transportation logistics.
Depot Activity Reports: Detailed reports on depot activities offer supply managers insights into inventory movements, storage conditions, and any incidents or discrepancies. This information facilitates proactive management, enabling prompt corrective actions and ensuring compliance with regulatory guidelines.
Conclusion
Drug pooling within the IRT world empowers supply managers with streamlined supply management, real-time shipment monitoring, and comprehensive reporting capabilities. By centralising drug inventory and providing detailed visibility into drug allocation, shipment activities, and depot operations, drug pooling optimises logistics and enhances data-driven decision-making. Supply managers can effectively allocate resources, monitor shipments, and ensure the smooth functioning of clinical trials within a programme of studies. Leveraging the power of drug pooling in the IRT domain accelerates research efficiency, reduces costs, and contributes to the successful execution of clinical trials.
By: Kathleen Williams, CPS Manager, Dan Ward, Product Manager
Recent updates to regulatory guidance (EU regulation 536/2014) mandate that clinical trial protocols include details regarding the tracing, storing, returning and destroying of all investigational products throughout the lifecycle of the trial. This mandate has moved accountability, reconciliation, returns and destruction from after thoughts to key considerations during the planning phase of a trial. End to end IP traceability arrangements need to be made and documented in trail protocols which in turn need IRB approval.
Almac’s ART™ feature can assist in organizing and defining these plans for trial leaders. ART™ makes planning for accountability, reconciliation and destruction seamless. It highlights all details needing consideration in advance and ensures the end-to-end traceability of investigational products is obtained.
What is ART™?
ART™ (Accountability & Reconciliation Tracking) is an electronic chain of custody solution that incorporates all IP events—from product release through to product destruction in a single system. It’s a single solution to comply thoroughly with GCPs and GMPs. ART™ features validations and flexible, configurable workflows that streamline the accountability and reconciliation processes.
Why do Almac’s clients select ART™?
The accountability and reconciliation process is known for being time-consuming and error-prone, two characteristics that result in it adding significantly to trial costs and timelines. The task of reconciling discrepancies in supply records that have accumulated over the course of a trial often adds as much as two years to the study closeout phase.
The effort to reconcile discrepancies before the destruction of kits at depots is magnified by the sites’ lack of compliance with accountability processes and tools. ART™ helps sites maintain compliance and complete records in order to significantly reduce discrepancies at the source.
Depots can now focus on managing their returns and destruction processes without the burden of identifying and resolving site issues. Supply managers can finally have real-time visibility into supply status and can monitor and report on compliance with Good Manufacturing Practices (GMP) without the need to construct complicated reports by collecting and assembling data from multiple sources.
What are the benefits?
ART™ helps sponsors and CROs realize time savings that come from easy setup, streamlined site operations, error reduction, and discrepancy resolution. Additionally, real-time validation checks at the time of dispensing and ongoing visibility to the condition of drug supplies throughout the supply chain improve compliance, reduce risk to patient safety, and safeguard against trial delays.
In fact, inadequate record keeping and inadequate accountability for IP are two of the most common issues cited in FDA warning letters.
Users can analyze and cross-reference patient records with supply records, all on a single screen. They can assess and report on the progress of the entire chain of custody, again in real time. And, they can perform root-cause analysis of issues relating to any IP event so they can address them as soon as possible.
What was being used before ART?
In many cases, accountability and reconciliation is still paper based, and in others it is supported by fragmented solutions that do not completely solve the problem. For example, accountability solutions that do not prevent discrepancies from creeping into data sets do little to improve reconciliation. Solutions that fail to link the drug assignment to the chain of custody records don’t provide a continuous, unbroken lineage of what was assigned, dispensed and returned, so they cannot confirm study compliance with regard to IP consumption.
In contrast, ART™ is integrated with the IXRS®3 system and provides visibility to, and an audit trail of, product conditions and movement throughout the trial. This improves patient safety, reduces trial risks, and strengthens monitoring and compliance while cutting costs and shortening timelines.
How do I fit ART to my standards?
ART™ is configurable to allow for 1 or 2 or even 3 step approval of accountability/reconciliation information. It can allow for correction of data during reconciliation or requesting for reaccounting. It can track consumption at the kit or unit (e.g. pill or other kit part) level. It can also be configured to report and alert for any discrepancies.
How can my trial achieve the best results?
Planning for accountability, reconciliation, returns and destruction of investigational product should be considered as important as planning for its release and distribution. Discussions related to this topic should be conducted as early in the lifecycle of a trial as possible. This will not only ensure compliance with EU regulation 536/2014, it will also save time and resources previously spent maintaining error-prone paper based systems.
During the design phase of your Almac IRT system, several considerations will be discussed in efforts to define and deliver an efficient vehicle to record the journey of all investigational product employed in a trial. Does IP need to be accounted for at a dosage unit level or a dispensing unit level? Will IP be returned and destroyed at sites? Or will IP need to be sent to a depot or other central location for destruction after being returned and accounted for at the site level? The Almac ART™ functionality is flexible enough to accommodate any combination of these scenarios.
ART™ guides users through steps to ensure complete collection of data and provides error-correction workflows— benefits that can only be realized when the system is used routinely. ART™ is best used as a trial progresses. It is not intended to be used sparingly or used just at study close out. Using ART™ as it is intended throughout the duration of a trial will result in accurate data collection and prevention of study close out delays.
The purpose of a UAT is to ensure the software, in this case IRT, was built to the specifications. Sponsors have a regulatory responsibility to perform UAT as outlined in EMA GCP 600788, Section 2.2.4.
UAT is your opportunity to get your hands on your custom-built solution to ensure it will meet your end users’ needs as you envisioned. This is not the time to ”Break the System” (your vendor team has likely already performed this), but you do want to run through transactions as your end-user would typically. You will want to ensure not only are the transactions completing as expected, but the associated reporting and data exports are accurate. If you do find any issues, UAT is a more cost-efficient check point to correct them prior to production use.
What are the keys to a successful UAT?
You will have limited time to execute your UAT and so you need to make sure you have a plan of action from the beginning of your project. You will also want to ensure your other vendor’s IRT integrated systems are ready at the same time to ensure your data is integrating across systems as expected, mirroring how the system will be utilized in production end-to-end. Partnering with a vendor with expertise on the UAT script creation process can help to streamline many of the activities that happen during this time.
Plan
Create a project plan: The IRT is just one system for your clinical trial. A best practice is to ensure your integrated systems are available in a UAT environment at the same time as your IRT. This will help you validate test files as you execute IRT transactions
Create your Subject Matter (SME) team: who will provide input and approval to the UAT strategy document and UAT test scripts? Who will help execute the scripts? What design enhancements or changes are dealbreakers to closing the UAT Phase? Who needs to give final approval to move the system Live?
Prepare
Review the software specifications and prepare the UAT testing scenarios you plan to cover during the software build in a UAT strategy document. The document should be a high-level list of key scenarios that must be covered in the plan. Once you have identified your strategy, get feedback on the UAT approach from your stakeholders including internal SME’s and external vendors. When all parties have reviewed and requirements are stable, you can draft your formal scripts off this scenario document.
Your test scripts should focus on Critical/High-Risk scenarios. Leverage your vendor’s core and configurable functionality to limit your testing to the customized areas of the software. A great place to bring efficiency into your script is to re-use data created earlier in the script for later transactions. For example, you can screen a subject and carry through Randomization, Kit Assignment Visits, and End of Treatment rather than using new subjects for each feature. A step further for more advanced UAT teams to consider is using test automation tooling to speed up repetitive processes such as subject data setup.
How will you execute your scripts?
There are several ways a UAT can be executed. Here are a few we recommend and considerations you may want to think about.
Independently: One user executes all scripts
Team based: Will the team use the same script or different scripts? What methodology will be followed? Here are a few types of team-based UAT processes we have seen in our experience:
UAT Methodologies
How will the team collaborate and communicate questions/challenges/concerns?
How technology can be harnessed to bring together virtual/global teams?
Perform
The clock is ticking! Execute your scripts and add extra ones as you think of more you missed. Communicate status with key stakeholders each day in summary form. Keep a log of issues/questions and close out any showstopper issues with the vendor prior to UAT completion. Defer any non-priority changes to a later version of the software as time allows.
Approve
When all parties have completed their tests and agree that the system was built to the approved requirements, you can now give approval to the vendor declaring the acceptability of the results and request that the system or change be moved to the live environment. Congratulations! You have successfully completed the UAT Phase and meeting your regulatory obligations to ensure suitability of the system!
Final Thoughts
User Acceptance Testing is a software process that gives sponsors the opportunity to run through real-world transactions prior to system launch. UAT functions as a cost-effective checkpoint that ensures efficiency, suitability, and end-user performance as envisioned.
What is Interactive Responsive Technology (IRT) data integration?
By definition, Interactive Responsive Technology (IRT) data integration is a mechanism to combine data from multiple source systems and add interoperability between systems. IRT is a vital trial data source and, therefore, directly responsible for sending/receiving data from one application to another. Clinical data integrations are often required as combining data from more than one eClinical system adds the necessary context needed to transform data into valuable and actionable information. Integrations also help build a more holistic view of all data for the end user.
How is IRT data sent?
Safe data transmission can use several communication protocols, file formats, and authentication methods. While Almac Clinical Technologies’ IX®S3 IRT system can accommodate all commonly used transmission methods, selecting suitable technical parameters depends on the systems’ capabilities involved in the integration.
Almac Clinical Technologies’ standards include as much automation and self-healing capabilities for data transmission as possible. We also strive for the most secure methods possible between the two integrated systems. These standards ensure the timely delivery of adequately protected data and require no manual intervention.
Sometimes the destination system, source system, or operational process IXRS 3 is integrating with does not possess the capabilities to meet these standards. Almac Clinical Technologies can accommodate these integrations once the associated risks are identified and accepted.
What types of IRT data integrations are most used?
IRT data integrations are contracts between two systems. Therefore, the delivery team must consider both systems’ capabilities in selecting the correct interface that works well with both sides of the integration.
Common examples of the systems IRT integrates with:
Electronic Data Capture (EDC)
Clinical Trial Management System (CTMS)
Clinical Supplies
Optimization
Central Labs
Clinical Assessment
Common integrations technical interfaces used:
Web APIs (REST)
Web services (SOAP)
Secure file transfer (SSH, TLS)
Web portal posting (HTTPS)
What considerations should be made?
Key considerations should be made when determining the data integration needs of your trial.
Generating Business Value
System interoperability and data sharing are two primary high-level purposes for integrations.
System interoperability is easiest defined as sending data between systems to drive action in the destination system. These integrations often have the highest business value as they do much more than sync data between systems. A simple example of system interoperability is screening a patient in IRT and sending the relevant data to create the patient and required eCRFs in the EDC system. In this model, each system owns and maintains its data.
Data sharing is syncing data between systems, most often to support reporting use cases. The shared data may also be required for actions in the destination system to occur but does not directly initiate those actions. If these integrations are carefully specified, it is easier to understand which system owns the data and is responsible for corrections and maintenance. For example, when a human makes a mistake in one system, these data-sharing integrations propagate those errors to other systems with little warning. These scenarios often require manual data changes in one or more systems.
Information Security
As with any secure system, credentials and authorization is a component of data integrations. It is important to consider that the ‘sender’ of a data integration is an application, such as the IXRS3 application. All account credentials are stored in a secure location, and access is restricted to staff who are trained on Data Services policies and procedures.
Providing account types for data integrations that have the same settings enforced as other individual user types is not ideal. For example, an account that is set to expire every 30 days by an end user will be managed during user log in attempts. For a data integration, an individual is not manually logging in. Accounts with these same settings will result in delays in receipt of data due to file failures, and additional support for managing password resets and account lock outs. These integrations should use service accounts that follow with the security policies for service accounts set by your organization’s information security professionals.
Data
Defining the exact data to be sent is critical to the success of the integration. Inclusion of additional data that is of no value to the specific analysis being performed will subsequently require additional processing to exclude the data.
Data may or may not be editable. When data can be edited, ensuring to account for how edits will be sent is important. Even properly working integrations will amplify human data entry errors by propagating the wrongly entered data across integrated systems. It is important to ensure that the systems have clear roles and responsibilities for correcting and editing data.
File Type Extension
Almac can submit data in all commonly required file types. Ensure to consider the file type that is required by the receiving system and/or the individual who will be receiving and analyzing the data. Receiving the data in the appropriate file type will avoid any unnecessary file type conversions.
Frequency
How often is the data needed? This may depend on the type of data, whether it be unblinded or blinded.
Just like any other user support, in its most basic form IRT support helps users solve problems, providing guidance on how to use the system, and answering users’ questions. IRT support specifically assists with these requests for each clinical trial to manage patient enrollment, manage drug supply activities, and strictly control sensitive information such as treatment arm and medication assignments to maintain study blinding.
Who Uses IRT Support?
There are sponsor users that can largely be grouped into three areas: study management, supply chain management, and data management. However, this group’s support needs are typically not as urgent as the group that generates most of the requests. It’s site users who drive the bulk of support requests as they look for assistance with registering patient visits and working through challenges related to drug supply at their site.
What Are the Most Popular IRT Support Requests?
Many requests consist of the typical software support needs like managing account details: username, email address, password management. But it also extends into areas that are niche to a clinical trial like challenges with site supplies, data integrations, study management, and site data management.
Examples related to site supply can be understanding why the system may be displaying a message stating low or no inventory available or assisting with returning supplies to inventory. The goal of the IRT support team is to ensure uninterrupted supply to the site and ultimately the patients.
Requests regarding data integrations can include troubleshooting errors generated when data is passed between the IRT and another system as well as resending data to assist with overcoming the previous failures.
Study management related needs cover guidance to ensure the intended outcome is achieved when completing these study administration transactions within the system. A member of the sponsor’s team should be making the changes in the IRT as is expected by the regulatory agencies to demonstrate full control and awareness of their trial.
An IRT should allow users to modify some data directly in the system, for example, subject demographic information. Data management requests will come into play when data that is controlled due to blinding considerations and potential for use in driving stratification and/or medication assignment that needs to be updated. In these instances, IRT support is there to assist in making those changes without compromising the blind or the patient, when approved.
What Is IRT Support’s Role in Today’s Clinical Trial Environment?
Clinical trials become more nuanced and the industry continues to see turnover in front line roles like site investigators and trial managers, so user support is becoming a more critical part of the overall IRT solution. Whether it be providing guidance for users to get started using the system or direction to complete a specific transaction in the system, IRT support will be the first point of contact to ensure these team members are able to effectively and efficiently complete day-to-day trial activities. The IRT support team will also act as an extension of the sponsor’s team to assist with ensuring regulatory expectations are met in that Primary Investigators are always in control and aware of changes to their data. And, most importantly, IRT support teams’ job is finding a solution to a problem when a user is trying to ensure patients receive their medication correctly and on schedule.
Replacing manual supply chain management with an IRT system has been proven to benefit patients, the sites they report to as well as clinical teams.
At the center of every clinical trial is a patient waiting to be dosed. Using an IRT to manage clinical supplies ensures success in getting the correct dose of the appropriate treatment to patients on time. IRT systems can be employed to project as far out as needed to meet the supply needs of each trial schedule. This ensures continuity in patient dosing and eliminates concerns for sites stocking out of IP. In addition, using a validated and automated system to project and orchestrate supply chain management in a clinical trial will prevent oversupplying of sites and potential related drug wastage/cost.
How does data help drive IRT supply chain functionality?
Metadata used to drive IRT supply chain functionality can be used to resolve challenges unique to sites and to the study itself. Sites may find themselves challenged with the ability to store a large amount of investigational product. IRT resupply approaches can be altered to send less IP more often so that sites are never overwhelmed with a large quantity to store. Likewise, the same resupply approaches can be edited to accommodate sites that may enroll at a fast rate. In those instances, larger quantities can be sent. Either way, using an IRT takes the manual monitoring of patients and sites out of the equation.
How does IRT help control costs?
Developing and maintaining an accurate forecast of product demand over the course of a clinical trial is essential to controlling costs. The IRT provides Supply Chain Managers with real-time updates of what is happening with patient enrollment and product inventory throughout the supply chain. This aids with budget preparation, prevents wastage that comes from stockpiling supplies, avoids the risk of stock-outs, and reduces emergency measures needed to replace expiring drugs.
An IRT can also keep track of product expiry dates and ensure there is sufficient time for the patient to take the medication before it expires. It can also send alerts to study managers if expirations are looming. This notification is particularly important with drugs that must be actively managed because they have short shelf lives. Perhaps most important of all, an IRT gives supply managers a global view of available supplies at main depot, secondary depot and site level. They can therefore adjust their inventory and distribution tactics to meet current trial conditions.
How are depots affected by an IRT?
Depots benefit from IRT supply chain management as well. An IRT can generate customized drug order forms specifically highlighting temperature needs to depot employees. Further, utilization of an IRT can safeguard the generation of drug order forms to specific and predefined recipients at a depot prior to depot cutoff times.
What are other advantages of using an IRT for Supply Management?
IRT systems can assist clinical teams in tackling more complex scenarios such as titrations, weight based dosing, and cross over treatments in a seamless fashion. Allowing IRT systems to calculate and forecast for these scenarios results in dosing subjects on time all the time while eliminating waste and reducing costs.
Another significant benefit of the IRT that is often overlooked, is facilitating the task of drug accountability, returns, and destruction. This process is still often done manually in many studies, which is tedious and time consuming. By switching the process electronically via the IRT, sites can save time, improve efficiency, and reduce data entry error.
In summary, IRT supply management capabilities ensure accurate and timely dispensation to subjects, supply optimization at the site and study levels while providing real time data to supply teams and minimizing costs.
Randomization is the process for how subjects are assigned to Treatment (groups, arms, etc.) in a clinical trial with introducing a deliberate element of chance. If randomization is not utilized or utilized inappropriately, then assumptions may be made on upcoming Treatment assignments. Knowledge of what Treatment is being assigned next can consciously or unconsciously influence decisions on whether to enroll a subject or which subject to enroll next. This influence is called Selection Bias. When properly implemented, Randomization protects against Selection Bias to ensure the observed Treatment effect is due to the Treatment itself and not due this bias.
Further, randomization helps achieve the required number of subjects per Treatment, which is also known Treatment Balance. With the random allocation of subjects throughout the trial, it is expected that each Treatment will have similar subjects for evaluation.
Interactive Response Technology (IRT) enables the global execution of randomization and medication management across multiple sites. This removes the need for site-specific code-envelopes and other burdensome manual randomization processes. Instead of relying on an unblinded contact to track randomization, the IRT maintains an auditable dataset including details of each subject’s randomization transaction.
Determining how to design randomization in the IRT begins by reviewing the clinical trial’s protocol. Typically, the protocol provides randomization details such as the Treatments, allocation ratio, number of subjects enrolled (sample size) and other information as applicable (e.g., stratification factors, cohorts, etc.).
This article focuses on the most common randomization methodologies implemented in IRT:
Central Randomization
Stratified Randomization with Blocks Pre-Allocated to Strata
Stratified Randomization with Blocks Allocated On-Demand to Sites
How is Central Randomization Methodology Implemented in IRT?
Central Randomization is when all subjects are randomized within the same scheme regardless of any subject characteristics or demographics. Clinical trials use a Central Randomization design when Treatment safety and efficacy is evaluatedacross all randomized subjects, and no sub-group analysis is planned. This evaluation requires Study-Level Treatment balance.
For an example, assume a protocol’s randomization design specifies:
Treatments: 2 (Active vs. Placebo)
Treatment Allocation Ratio: 1:1
Sample Size: 20
Stratification: None – N/A
To obtain the Study-Level Treatment balance given the sample size (N=20) and ratio (1:1), the IRT will need to randomly allocate 10 subjects to Active and 10 subjects to Placebo. This is achieved via a Blocked Randomization List, sometimes referred as Randomization Schedule. The Randomization List is generated with a specified BlockSize that includes randomly ordered Treatment assignments within each block. For example, if the Block Size is 4, then for every 4 records, 2 Active records and 2 Placebo records would appear in random order. This blocking technique is the basis for each type of Randomization List utilized across the 3 common Randomization Methodologies. See below for an illustration of a Blocked Randomization List for Central Randomization.
Example 1: Central Randomization List
Sequence Number
Randomization Number
Treatment Code
Treatment Description
Block Number
SubjectID
10001
10001
A
Active
1001
1
10002
10002
A
Active
1001
2
10003
10003
B
Placebo
1001
3
10004
10004
B
Placebo
1001
10005
10005
A
Active
1002
10006
10006
B
Placebo
1002
10007
10007
A
Active
1002
10008
10008
B
Placebo
1002
10009
10009
B
Placebo
1003
10010
10010
B
Placebo
1003
10011
10011
A
Active
1003
10012
10012
A
Active
1003
10013
10013
B
Placebo
1004
10014
10014
A
Active
1004
10015
10015
B
Placebo
1004
10016
10016
A
Active
1004
10017
10017
B
Placebo
1005
10018
10018
A
Active
1005
10019
10019
A
Active
1005
10020
10020
B
Placebo
1005
The assignment of subjects to the randomization records in the IRT is simple! At randomization, the IRT identifies the next available record (based Sequence Number order) and assigns to the subject. The subject’s ID is permanently linked to their assigned Randomization Number and Treatment.
Looking at the Central Randomization design in the Example 1 list, the 1st, 2nd, 3rd subjects are assigned to Treatments A, A, and B, respectively. The 4th subject will be assigned to Treatment B, which will complete the block. When all 20 subjects are assigned, 5 blocks will be completed and Treatment allocation ratio of 1:1 will be maintained at the overall Study-Level.
What if a Clinical Trial Requires Sub-Group Level Treatment Arm Balance?
If Treatment effect differences are expected across certain subject sub-groups, then the randomization design may need to maintain the Treatment Balance within specified subject sub-groups. The clinical trial’s protocol defines these sub-groups as Stratification Factors. This sub-group level balance can be achieved within a Stratified Blocked Randomization List.
For an example, assume a protocol’s randomization design specifies:
Treatments: 2 (Active vs. Placebo)
Treatment Allocation Ratio: 2:1
Sample Size: 90
Stratified by:
Prior Treatment (Yes vs. No)
Symptom Score: (1 vs. 2 vs. 3)
Based on the above details, approximately 60 subjects will need to be assigned to Active, and 30 subjects assigned to Placebo. Within each cross-combination of the protocol’s Stratification Factor Levels (defined as Stratum), the blocks should maintain the 2:1 Treatment allocation ratio. The Randomization List for this study can be designed with a Block Size of 6 (with 4 Active and 2 Placebo records) and the below Stratum definitions:
Stratum
Prior Treatment
Symptom Score
Stratum Description
1
Yes
1
Prior Treatment: Yes; Symptom Score: 1
2
Yes
2
Prior Treatment: Yes; Symptom Score: 2
3
Yes
3
Prior Treatment: Yes; Symptom Score: 3
4
No
1
Prior Treatment: No; Symptom Score: 1
5
No
2
Prior Treatment: No; Symptom Score: 2
6
No
3
Prior Treatment: No; Symptom Score: 3
Each Stratum is pre-allocated its own set of randomized blocks within the Randomization List, which essentially creates a sub-list for each Stratum. Example 2 below shows the 1st block in the Stratum 1 sub-list and the 1st block in the Stratum 6 sub-list.
Example 2: Stratified Randomization List with Blocks Pre-Allocated to Stratum
Sequence Number
Randomization Number
Stratum
Stratum Description
Treatment Code
Treatment Description
Block Number
SubjectID
10001
10001
1
Prior Treatment: Yes; Symptom Score: 1
A
Active
1001
1
10002
10002
1
Prior Treatment: Yes; Symptom Score: 1
A
Active
1001
10003
10003
1
Prior Treatment: Yes; Symptom Score: 1
B
Placebo
1001
10004
10004
1
Prior Treatment: Yes; Symptom Score: 1
B
Placebo
1001
10005
10005
1
Prior Treatment: Yes; Symptom Score: 1
A
Active
1001
10006
10006
1
Prior Treatment: Yes; Symptom Score: 1
A
Active
1001
…
…
…
…
…
…
…
…
60001
60001
6
Prior Treatment: No; Symptom Score: 3
B
Placebo
6001
2
60002
60002
6
Prior Treatment: No; Symptom Score: 3
A
Active
6001
60003
60003
6
Prior Treatment: No; Symptom Score: 3
A
Active
6001
60004
60004
6
Prior Treatment: No; Symptom Score: 3
A
Active
6001
60005
60005
6
Prior Treatment: No; Symptom Score: 3
A
Active
6001
60006
60006
6
Prior Treatment: No; Symptom Score: 3
B
Placebo
6001
…
…
…
…
…
…
…
…
To randomize subjects, the IRT first determines the subject’s Stratum, then identifies that Stratum’s sub-list and assigns the next sequential record. If the 1st subject has Prior Treatment = Yes and Symptom Score = 1, then they are assigned to Randomization Number 10001 and Treatment A. If the 2nd subject has Prior Treatment = No and Symptom Score = 3, then they are assigned to Randomization Number 60001 and Treatment B. As subjects are randomized within each Stratum, the blocks assignments are completed and the ratio of 2:1 is sustained.
Is this the only way IRT can randomize subjects within Stratification Levels?
NOPE!
The pre-allocation of blocks to stratum demonstrated above is the most common method for stratified randomization, but there are situations where pre-allocation is not the best fit.
When Site is a Stratification Factor, it is highly possible that more Sites are added mid-study. If pre-allocating blocks to Site (creating a sub-list for each Site), then each time a Site is added in the IRT, a new list would also be needed. This incurs unnecessary downtime and subsequent costs.
To avoid this headache, utilize On-Demand Allocation of Blocks to Sites! The list is generated in the same way as the Central Randomization List in Example 1, with no blocks pre-allocated to any specific Site. Then the IRT allocates blocks to each Site On-Demand.
As an example, assume a protocol’s randomization design specifies:
Treatments: 2 (Active vs. Placebo)
Treatment Allocation Ratio: 1:1
Sample Size: 100
Stratified by: Site
A Blocked Randomization List with a Block Size of 4 is generated without any blocks pre-allocated to Sites. At Randomization, the IRT first checks if any blocks with available records exist for the subject’s Site. If no, then the IRT identifies / assigns the next set of available Block(s) to the subject’s Site and assigns the 1st record to the subject. If yes, then the subject is assigned to the next available record within the block(s) allocated to their Site.
The number of blocks to assign to each Site can be set based on each study’s preference. For ease, the example will demonstrate allocating just 1 block at a time.
Assume the 1st 3 subjects are at the following Sites:
SubjectID=1, Site 1234
SubjectID=2, Site 3232
SubjectID=3, Site 1234
Since the 1st subject is at Site 1234, the 1st Block (1001) is assigned to Site 1234. SubjectID = 1 is assigned to the 1st record in that Block (Randomization Number 10012, Treatment A). The 2nd subject is at Site 3232, the IRT assigns the 2nd Block (1002) to the Site and 1st record in that Block (Randomization Number 10006, Treatment B) to SubjectID = 2. The 3rd subject is at Site 1234, which has records available for assignment, thus the 2nd record in Block 1001 is assigned (Randomization Number 10004, Treatment B) to SubjectID = 3.
Example 3: Stratified Randomization with Blocks Allocated On-Demand to Stratum (Site)
Sequence Number
Randomization Number
Treatment Code
Treatment Description
Block Number
Site
SubjectID
100001
10012
A
Active
1001
1234
1
100002
10004
B
Placebo
1001
1234
3
100003
10002
B
Placebo
1001
1234
100004
10001
A
Active
1001
1234
100005
10006
B
Placebo
1002
3232
2
100006
10011
B
Placebo
1002
3232
100007
10009
A
Active
1002
3232
100008
10007
A
Active
1002
3232
100009
10005
B
Placebo
1003
100010
10008
A
Active
1003
100011
10003
A
Active
1003
100013
10010
B
Placebo
1003
As shown above, this approach sets up the Site stratification within the Blocked Randomization List On-Demand. In this design, the IRT can allocate blocks to new Sites (or even Stratum!), without having to generate subsequent Randomization Lists.
How Should Randomization Numbers be Ordered in the Randomization List?:
For simplicity, in the Examples 1 and 2, the Randomization Number is ordered sequentially and equal to the Sequence Number. However, it may be necessary for Randomization Numbers to appear in random (Scrambled) order for blinding purposes. Example 3 (On-Demand Allocation of Blocks to Sites) warrants Scrambled Randomization Numbers since it involves assigning a single block at a time. Scrambling the Randomization Numbers prevents anyone from identifying the Block Size. In the example, if the Randomization Numbers were ordered sequentially, study personnel may be able to figure out that Randomization Numbers are assigned in sets of 4, which is equal to the block size. To scramble or not to scramble should be agreed upon by sponsor’s Biostatistical Representative and the IRT List Generators.
Important: The Block Size is an Unblinding Parameter that should only be known to study personnel involved in the design and implementation of the Randomization List. Knowledge of the block size can lead to potential Selection Bias!
Final Thoughts:
The IRT randomization list approaches discussed in this article are just the surface of randomization possibilities! More complex methods for randomization are achievable through IRT (e.g., Covariate Adaptive Randomization (minimization), Target Adjusted Algorithms, Hierarchal Algorithms, Adaptive Designs, Master Protocols, etc.).
What is Interactive Response Technology (IRT) or Randomization and Trial Supply Management System (RTSM)?
An IRT system is known by many other names such as IVRS, IWRS, IXRS, RTSM but regardless of its name, the system delivers a wide range of features for managing patient enrollment and drug supply activities throughout the clinical trial lifecycle.
What are the benefits of using IRT to Support Patient Enrollment into a Clinical Trial?
Patient Enrollment, Randomization and Blind Protection – Utilizing the IRT to handle the enrollment and/or randomization automates the process and eliminates human error compared with manual methods. The system allows for complex protocol enrollment and randomization design and strictly controls sensitive information such as treatment arm and medication treatment assignments to maintain study blinding.
How are Patients Randomized using IRT?
The IRT will systematically randomize patients by assigning them to a treatment arm. There are several common methodologies which can be used such as central, subject stratified and/or site stratified randomization schemes. At the randomization visit, the IRT will assign the subject the appropriate treatment arm based on the programmed randomization methodology. The IRT will typically also assign the subject the appropriate medication kit which matches the randomized treatment arm.
What if I Choose not to use an IRT for Randomization?
To truly appreciate how efficiently an IRT randomizes patients in a double-blind trial, just look at how it was done prior to the availability of IRT. When an IRT is not utilized, each entry on the patient randomization list is associated with a treatment type and matching kit number. The number is sealed in an envelope bearing a sequence number. A block of envelopes and the associated kits are sent to the investigational site where envelopes are chosen in sequence. The matching kit is then dispensed to the patient. While this method is reasonably efficient on an extremely small scale, it is slow and only works with simple randomization designs. Plus, it is subject to human error. When IRT handles randomization, the process is automated and centralized. It can accommodate complex stratification and randomization design that would not be possible with manual randomization. Randomization happens without human intervention, and therefore reduces human error. And, as with other aspects of study management, the system stores the data for easy tracking. Automating the randomization and drug assignment process eliminates the need for paper envelopes or cards to be stored at the site where unblinded information could be compromised.
How does the IRT help protect the study blind?
An important function of the IRT is to protect unblinded study data from being disclosed inappropriately. For blinded studies, maintaining the blind is pivotal to the integrity of the trial because it eliminates bias in how patient is treated. Without this protection, the study results can be invalidated. Overall, the IRT acts almost as a force field that shields unblinded information, such as the treatment arm and medication type, from those who should not be privy to it. Access to functions in the system is controlled based on user privileges, so only users who should be privy to unblinded data in the IRT can view it. As with all of the activity recorded through the IRT, this information can be transferred to, or integrated with, another system. Controls are put in place so that unblinded data can only be sent securely to the intended recipient.
What About Emergency Unblinding?
The IRT commonly includes emergency unblinding functionality. This can be setup so that Principal Investigators are able to unblind patients at their sites in case of an emergency. When an emergency code break by the site occurs, the system immediately notifies the study team. Often times, that patient who was unblinded by the site is then automatically discontinued from the study, preventing further drug assignments by the IRT. The IRT can also provide access to the Medical Safety team who can unblind any patient at any site without impacting their ongoing participation in the study.
What are the benefits of using IRT for Supply Management?
Individual kits stored at the depot and site are not labeled for particular patients. Instead, kits are assigned to patients when they arrive for their visit. So, shipments to sites only contain enough product to meet patient demand over a certain period, and resupplies are triggered when inventories hit a designated level. This process maximizes drug availability at the site, since products are only allocated to patients when they come in for visits and minimizes drug wastage. The IRT is able to tailor the supply provided to each site since it knows what patients are at each site, their treatment arms, and the visit schedule.
Developing and maintaining an accurate forecast of product demand over the course of a clinical trial is essential to controlling costs. The IRT provides Supply Chain Managers with real-time updates of what is happening with patient enrollment and product inventory throughout the supply chain. This aids with budget preparation, prevents wastage that comes from stockpiling supplies, avoids the risk of stock-outs, and reduces emergency measures needed to replace expiring drugs.
An IRT can also keep track of product expiry dates and ensure there is sufficient time for the patient to take the medication before it expires. It can also send alerts to study managers if expirations are looming. This notification is particularly important with drugs that must be actively managed because they have short shelf lives. Perhaps most important of all, an IRT gives supply managers a global view of available supplies at main depot, secondary depot and site level. They can therefore adjust their inventory and distribution tactics to meet current trial conditions.
How does IRT Provide Inventory Management?
The IRT has a variety of features to manage the chain of custody of supplies in a trial – from the time supplies are packaged and released at the depot through to medication assignment as well as drug returns and destruction. After supplies are physically packaged and made available in the system, initiation and tracking of movement to another depot or site occurs. As soon as the Sponsor activates a site in the IRT, the system triggers a request to the depot for an initial supply of medication. The depot fills the order and sends the shipment to the site. When an order arrives at the site, staff confirm its receipt in the IRT, and the drugs are made available for assignment to patients. As patients visit the site, they are assigned a medication kit from the site’s inventory. All the while, an algorithm within the system is monitoring the inventory at each site. If the inventory reaches a pre-determined low level, the supply engine will generate a request for the depot to send a resupply. Through this closed loop process, shipments are made to accommodate newly enrolled patients, subsequent visits, and any needed replacement stock.
Another significant benefit of the IRT that is often overlooked, is facilitating the task of drug accountability, returns, and destruction. This process is still often done manually in many studies, which is tedious and time consuming. By switching the process electronically via the IRT, sites can save time, improve efficiency, and reduce data entry error.
How does IRT help with Patient Tracking and Reporting?
All patient and supply data stored in the IRT database are readily available in the form of reports and data lookups. This enables the clinical and drug management team to have access to real-time data, study metrics, and alerts. This allows ease of review of the study as it progresses and to subsequently make any necessary adjustments to things like the enrollment or site’s inventory settings to meet the specific condition of the trial at any given time.
Final Thought:
Essentially, an IRT increases trial efficiency and improves the quality of available information throughout a trial.
