Author: brendanhagan

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.

By:

Jennifer Ross

CT PA Director of Biostatistics

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.