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 trial 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. ART™ 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.
Evidence shows that replacing manual supply chain management with an IRT system benefits patients, the sites they report to as well as clinical teams.
At the centre of every clinical trial is a patient waiting to receive dosage. 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 of particular importance for drugs with short shelf lives that require active managing. 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 an IRT affect depots?
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 IRT often overlooked, is facilitating the task of drug accountability, returns, and destruction. Done manually in many studies, this process is both 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.
Randomisation 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 randomisation 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, Randomisation protects against Selection Bias to ensure the observed Treatment effect is due to the Treatment itself and not due this bias.
Further, randomisation 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 randomisation and medication management across multiple sites. This removes the need for site-specific code-envelopes and other burdensome manual randomisation processes. Instead of relying on an unblinded contact to track randomisation, the IRT maintains an auditable dataset including details of each subject’s randomisation transaction.
Determining how to design randomisation in the IRT begins by reviewing the clinical trial’s protocol. Typically, the protocol provides randomisation 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 randomisation methodologies implemented in IRT:
Central Randomisation
Stratified Randomisation with Blocks Pre-Allocated to Strata
Stratified Randomisation with Blocks Allocated On-Demand to Sites
How is Central Randomisation Methodology Implemented in IRT?
Central Randomisation is when all subjects are randomised within the same scheme regardless of any subject characteristics or demographics. Clinical trials use a Central Randomisation design when Treatment safety and efficacy is evaluated across all randomised subjects, and no sub-group analysis is planned. This evaluation requires Study-Level Treatment balance.
For an example, assume a protocol’s randomisation 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 Randomisation List, sometimes referred as Randomisation Schedule. The Randomisation 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 Randomisation List utilized across the 3 common Randomisation Methodologies. See below for an illustration of a Blocked Randomisation List for Central Randomisation.
Example 1: Central Randomisation List
Sequence Number
Randomisation 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 randomisation records in the IRT is simple! At randomisation, 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 Randomisation Number and Treatment.
Looking at the Central Randomisation 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 randomisation 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 Randomisation List.
For an example, assume a protocol’s randomisation 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 Randomisation 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 randomised blocks within the Randomisation 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 Randomisation List with Blocks Pre-Allocated to Stratum
Sequence Number
Randomisation 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 randomise 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 Randomisation Number 10001 and Treatment A. If the 2nd subject has Prior Treatment = No and Symptom Score = 3, then they are assigned to Randomisation Number 60001 and Treatment B. As subjects are randomised within each Stratum, the blocks assignments are completed and the ratio of 2:1 is sustained.
Is this the only way IRT can randomise subjects within Stratification Levels?
NOPE!
The pre-allocation of blocks to stratum demonstrated above is the most common method for stratified randomisation, 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 Randomisation 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 randomisation design specifies:
Treatments: 2 (Active vs. Placebo)
Treatment Allocation Ratio: 1:1
Sample Size: 100
Stratified by: Site
A Blocked Randomisation List with a Block Size of 4 is generated without any blocks pre-allocated to Sites. At Randomisation, 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 (Randomisation 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 (Randomisation 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 (Randomisation Number 10004, Treatment B) to SubjectID = 3.
Example 3: Stratified Randomisation with Blocks Allocated On-Demand to Stratum (Site)
Sequence Number
Randomisation 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 Randomisation List On-Demand. In this design, the IRT can allocate blocks to new Sites (or even Stratum!), without having to generate subsequent Randomisation Lists.
How Should Randomisation Numbers be Ordered in the Randomisation List?:
For simplicity, in the Examples 1 and 2, the Randomisation Number is ordered sequentially and equal to the Sequence Number. However, it may be necessary for Randomisation Numbers to appear in random (Scrambled) order for blinding purposes. Example 3 (On-Demand Allocation of Blocks to Sites) warrants Scrambled Randomisation Numbers since it involves assigning a single block at a time. Scrambling the Randomisation Numbers prevents anyone from identifying the Block Size. In the example, if the Randomisation Numbers were ordered sequentially, study personnel may be able to figure out that Randomisation 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 Randomisation List. Knowledge of the block size can lead to potential Selection Bias!
Final Thoughts:
The IRT randomisation list approaches discussed in this article are just the surface of randomisation possibilities! More complex methods for randomisation are achievable through IRT (e.g., Covariate Adaptive Randomisation (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.
The pharmaceutical industry’s current drug development system is “in crisis and unsustainable”, according to the Clinical Trials Transformation Initiative (CTTI), a public-private partnership in the US to improve the quality and efficiency of clinical trials.1 The organization has, over the past few years, issued multiple sound recommendations for Sponsors and Contract Research Organizations (CROs) on a range of trial processes—from recruitment planning to data monitoring.
Meanwhile, Sponsors and CROs are actively pursuing various trial innovations that can ultimately lead to a competitive advantage in the market. However, there is a frequent source of inefficiency in clinical trial operations that is often overlooked: the lack of coordination between the digital and the physical supply chain of drug delivery to trial sites.
The integrated supply chain
The pharmaceutical industry is accustomed to thinking of the clinical trial supply chain as having two distinct parts: the digital supply chain, meaning the technology required to manage and monitor drug inventory, and the physical supply chain, or the processes involved in preparing and shipping drug products from depots to sites. That delineation was created—and is now perpetuated—not for any process-related reason, but rather simply because most vendors supporting the industry provide only half of the equation.
The delineation between the digital and physical supply chain need not exist; ideally, it should not exist. The digital and physical aspects of the supply are inexorably linked across all phases of the trial, starting with forecast and moving onto the bulk input and preparation of finished goods ready to ship from the depot… to monitoring sites’ inventory and patient dispensing… to managing returns and accounting for the disposition of all products. There are significant interdependencies between the Interactive Response Technology (IRT) and the management services needed to ensure that the right drug is available at the right site at the right time, and for the lowest cost.
The extent to which the supply chain technology and supporting services are integrated directly affects the amount of oversight, degree of alignment, number of custom system integrations and level of risk involved in ensuring successful trial operations. A greater coordinated effort will lead to more visibility into what is happening and thus enable the trial manager to meet the trial demands in a more cost-effective, streamlined way. Conversely, executing the optimal supply chain strategy is more difficult, expensive, and time-consuming when different vendors are working independently.
When trial Sponsors turn to separate partners to support the digital and physical supply chain, they must necessarily commit to spending significant management time serving as a go-between. The onus is on the Sponsor to ensure that the lines of communication are open between all of the parties, which usually translates into more frequent meetings.
Having multiple vendors also contributes to a fragmented financial picture. As explained by Heather Schultz in an Applied Clinical Trials article, “Multiple vendors and contracts end up in disparate systems, and the lack of integration doesn’t allow that data to be brought together for financial management in an easy or efficient way, making forecasting and budgeting extremely challenging.”
The complexity of problem resolution also increases with the number of vendors involved in the project. Multiple information sources and the limited view of each vendor make root cause analysis difficult. Also, it is easy for individual vendors to lapse into absolving themselves, pinning the “blame” for issues on others.
Finding a workable resolution can, therefore, be frustrating and time-consuming. In contrast, when a single vendor team is involved throughout the project, there can be a single, cross-team escalation pathway that tends to speed problem resolution.
Alignment, coordination, and consistency
The above project oversight issue has easy remedies but can require costly investment with the help of additional management resources. However, the need to ensure that all parties are in alignment and are working toward a common goal using consistent approaches is a much more serious matter.
A common understanding of the strategy is essential to seeing that the IRT design, packaging design, and distribution strategy all are working together in a cohesive fashion. Costly inefficiencies arise when elements are misaligned. The Investigational Medicinal Product (IMP) may sit at the depot long before the IRT is configured, or vice versa. The IRT may generate shipments that are impractical for sites to cope with logistically or that are not in line with the average patient’s treatment needs. Each vendor is able to create its own, unrelated set of requirements, not easily integrated with others, that generates difficulties for supply monitoring and data analysis. And the list goes on.
Vendor responsibility is limited to the portion of the overall trial they have visibility to. Therefore, ensuring that overarching protocol objectives are met rests with the study Sponsor. Ensuring that cross-discipline goals, timelines, processes, and deliverables align across vendors is a time-consuming and challenging endeavor. Efficiencies in Clinical Trial delivery translate into increased quality and decreased cost.
In the foreseeable future, biopharmaceutical companies that do not allow those working on clinical trials to have mobile access to the systems and data they need will be at a competitive disadvantage.
Internal users, investigator sites, Clinical Research Organizations (CROs), central labs, and other vendors all have a growing expectation that they can access trial data and applications “where they live,” in other words, on their mobile devices. Indeed, worldwide usage trends and prospective productivity gains make a compelling case for moving in a mobile direction. However, some inherent security risks complicate the landscape significantly, and decision-makers should proceed with their eyes wide open. Here, we discuss the leading security risks to consider and offer recommendations on how to mitigate or avoid them.
The case for mobile access
Mobile devices are now ubiquitous, with their usage long since eclipsing that of desktop devices. The crossover happened in 2014, and the gap continues to widen in favor of mobile computing.1 What is more, over the past five years, there has been a substantial increase in the number of Internet users who rely exclusively on mobile devices.2
Cisco Systems was forecasting that by 2019, about 24 exabytes (a billion gigabytes) of data will be transferred to and from mobile devices each month.3 To put this intangible number into perspective, consider that a single Exabyte could transmit 119 billion songs that would last for 906,000 years.4
Between 2012 and 2015 there has been double-digit growth in the number of clinical trials in most regions of the world. The Asia Pacific region has seen material clinical trial growth led by countries like China (71%), Japan (54%), and India (37%). This growth in clinical trial volume is from the region that is forecasted to have the most significant mobile data volume over the next five years.
Given the popularity of mobile devices, it is no wonder that those involved with clinical trials—and most especially clinical investigators—would prefer to have the information and tools that they need to do their jobs accessible on smartphones and tablets. For instance, it is much more efficient for investigators to be able to work with clinical trial tools that are embedded in their workflow for providing the standard of care than it is for them to have to switch systems and transport data from one device to another.
Healthcare institutions have captured the attention of cybercriminals for several reasons:
The exchange of electronic healthcare information is a relatively recent phenomenon, and many institutions are still soft
Healthcare databases contain vast amounts of Personally Identifiable Information (PII) that doesn’t “expire.”
Credit card and bank account data present only a narrow window of opportunity—i.e., typically the theft is discovered and the breach remedied quickly. Meanwhile, medical information fraud can go undetected for quite some
Many financial services institutions and retailers have developed some expertise and experience in thwarting attacks, so criminals turn their attention
The value of stolen healthcare data is at a
According to the World Privacy Forum, hackers and identity thieves will pay $50 for stolen medical information versus $1 for a stolen Social Security 5
The sources of risk: BYOD and outside networks
Bring Your Own Device (BYOD) solutions
At first blush, allowing those involved in clinical trials to use their own existing mobile devices (smart phones and tablets) for trial work and participation seems like a financial “no brainer.” Why provision and then have to maintain and manage proprietary devices when parties already have the hardware themselves? It is not as simple as it sounds, however. The main issue relates to the number of device platforms that would have to be supported, particularly for global trials. Not only is there the matter of Android versus Apple operating systems, but there are multiple releases of each on the market. (This is especially true in Latin America where the secondary market for used devices is very strong.) Not all will have the latest security patches.
Public hotspots and guest networks
Any data that resides on a device used in a public place is at risk of compromisation. From an executive checking their e-mail in a café, or a study monitor reviewing files at an airport. Usually, however, the device itself and the information on it are not the hacker’s ultimate target. Rather, hackers troll such networks in an attempt to use the mobile device as a vector to gain access to an organisation’s internal network.
Allow us to secure your mobile devices used in clinical trials through OVERSIGHT.
In the race to improve speed and efficiency in drug development, clinical research studies have grown dramatically in the last decade in both numbers and complexity. Adaptive design, multiple cohorts, randomization and detailed dosing instructions have been driving factors in this increase as sponsors are looking to achieve more endpoints within a single protocol.
As companies continue to collect higher volumes of data in an effort to shorten the duration and number of trials required for submission, it becomes increasingly difficult for researchers to manage this information. This means the toolsets used to conduct studies are being relied upon more heavily. At the same time, the pharmaceutical landscape continues to shift toward large molecule compounds, where a unique set of challenges is emerging. Compared to small molecule drugs, biologics are more sensitive to temperature shifts, making supply chain management increasingly difficult.
Additionally, not only are there higher costs to manage when developing a biologic, but also the submission of a Biologics License Application (BLA) is subject to higher scrutiny by regulatory agencies. Therefore, biologics inherently require an increased focus on Interactive Response Technology (IRT) processes by regulators, as the data collected in an IRT is crucial to support a regulatory submission. This is why now, more than ever, the FDA is taking a closer look at IRTs and how these systems can directly impact patient safety and clinical trial integrity. The obvious conclusion is that the partner chosen to provide the technology to assist with these challenges must be up for the task.
In today’s pharmaceutical market, nearly 20 percent of total sales are biologics. By 2020, it was expected that they will make up slightly more than half of the world’s top 100 selling drugs. As we move toward the future, the industry will look to technologies like IRT to meet the needs of the trials that will bring these drugs to market. In the competitive pool of IRT providers that have developed during the system’s evolution, how many will be able to offer the technologies, design, and experience to do this successfully?
FDA expectations of an IRT system
The IRT system captures the broader features emerging within the market, such as electronic-reported outcomes, titration/dosing calculations, shamming (blinding of patient labs or other results), supply accountability, reconciliation, and returns. It can ensure the drug is at the right place, at the right time, and in the right quantities with the ability to respond to any changes throughout the course of the trial. The information collected and generated in an IRT system is at the center of some of the most critical aspects of a clinical trial, such as:
Integrity of randomization, implementation, and stratification of data
Dosing calculations and/or titration rules
Supply management aspects, such as control of expiring drugs, tracking of temperature excursions, and management of recalls
Beyond these, an IRT system improves the visibility that sponsors have into how sites are performing. For this reason, the FDA expects it to be used as a way to provide proper oversight of a clinical trial and to identify and remediate issues in a timely manner.
There are many vendors trying to use IRT in a very simplistic way and focusing solely on randomization and supply management. However, IRT saves time and money across many aspects of trial execution, and it has the potential to do even more. The use of analytics from IRT to support risk-based monitoring decisions in a controlled and objective manner is one of them. In addition, proactive identification of supply challenges or non-compliance with supply usage can save thousands or even millions of dollars. The mobile capability of IRT systems will enable even further uses, making the technology work better within a site or patient workflow than any other technology available.
There are few vendors that understand the challenges of clinical trials and the opportunity IRT has to enable these trials to run effectively. As the go-to provider for complex studies that have emerged flawlessly from the FDA’s first IRT audit, Almac has the experience, expertise, and integrity required to deliver the results necessary to bring your drug to the patients who need it.
