Since ICH-GCP E6 R2 made Risk-Based Quality Management (RBQM) ‘official’ back in 2017, we’ve seen an increased uptake, especially through the pandemic in decentralized (DCT) or hybrid trials. This is because it has enabled sponsors to have the right framework in place to really focus on what matters most, and anticipate where there may be areas of concern, enabling more proactive management of trials.
When assisting clients in developing and/or executing their trial plan, Cmed’s aim in trial design is to find a balance between acceptable risks, practicalities, and financial impact. Our RBQM and Trial Operations Planning Standard Operating Procedures (SOPs) outline the framework for these trade-offs. Thus, we incorporate Quality by Design (QbD) in overall planning from the inception of a project and RBQM in conduct/execution to fully integrate ICH-GCP E8R1 and E6R2/R3 at the operational level. The overall benefit of this approach is having established a project-specific infrastructure that provides the operational mechanism for proactive risk management, with downstream effects on timelines and mitigating financial risk.
Whilst the implementation of RBQM is growing, the use of the term ‘risk’ in RBQM could still be hindering implementation or buy-in within organizations because a risk may be thought of as ‘bad’. However, a risk is merely a potential future issue, while an issue is a current problem that requires resolution.
Today, many industry resources focus on how to approach RBQM and why sponsors should be moving to implementation, including interpreting what is required and how to get started. However, these articles tend to cover items 5.0.1 through to 5.0.4 as per ICH-GCP E6 R2, when in fact the true “heavy lifting” starts at Sections 5.0.5: ‘Risk Communication’ and 5.0.6: ‘Risk Review.’ This article takes a more in-depth look at these two sections to show how the implementation of RBQM can reduce issues and achieve holistic trial oversight in today’s complex decentralized trials.
Section 5.0.5 relates to Risk Communication. As stated in ICH-GCP E6 R2, “The sponsor should document quality management activities, communicate quality management activities to those who are involved in or affected by such activities, and facilitate risk review and continual improvement during clinical trial execution.”
Documenting and communicating quality management activities is not new; it refers to trial documentation and communication channels such as risk assessment tools, Functional Plans, Visit Reports, Automatic & Manual Data Checks, Trial Operational Plans, and even team training and team meetings. What it does allow trial teams to understand is, who is looking at what data, when, why, and how.
We haven’t always had that level of cross-functional visibility. RBQM is encouraging teams to break down the siloes between each function, providing a holistic understanding and insight into how patient safety and reliability of trial results are being managed and overseen. This is underpinned at Cmed by the RBQM process requiring participation from all functional leads.
At Cmed, our RBQM process is embedded within the cross-functional trial team, providing a significant focus on patient safety, data reliability, and data integrity. Context and critical thinking are essential elements that form part of the RBQM process. Having RBQM embedded into the study team means the context of the study and certain situations are well known, allowing critical thinking to be applied to determine the most appropriate actions to be taken. Whilst the Project Leader has responsibility to ensure the RBQM process is followed for the trial, all functional leaders in the trial team have a vital part to play. We find that this approach allows us to truly embed RBQM into the daily running of the trial, and encourages accountability within the trial team, rather than having a separate role (usually referred to as a ‘Risk Manager’) overseeing this on behalf of the trial team. In turn, empowering the functional team to all be involved in this process enables quicker detection of potential risks becoming an issue, allowing solutions to be found, therefore preventing time wasted on managing issues.
Regarding decentralized trials, data is being collected from a multitude of non-traditional sources. Applying the RBQM process aids the trial team in understanding the journey of the identified critical data point(s), which functions are ‘touching’ that critical data point as it travels on that journey, and where the potential risks are on that journey that need to be considered and controlled. The expert Data Scientists at Cmed play a pivotal role in the RBQM process by helping to guide the wider cross-functional team to implement the most appropriate risk control strategies that keep patients safe and trial results reliable.
ICH-GCP E6 R2 Section 5.0.6 describes Risk Review as “The sponsor should periodically review risk control measures to ascertain whether the implemented quality management activities remain effective and relevant, taking into account emerging knowledge and experience.” So as soon as trial teams begin to receive clinical and operational data from their trials, the evaluation of the effectiveness of the initial risk assessments begins as part of Section 5.06: ‘Risk Review’.
Up until this point, the initial risk assessment (Sections 5.0.1 – 5.0.4) has been based on theory, with some application of previous experience. However, it is just theory, so it is very important to review and interpret data and operational information as your trial begins. The team now has visibility to what is truly happening, can contextually evaluate the effectiveness of their risk controls and respond accordingly.
Decentralized trials rely heavily on the receipt of data generated by a variety of different sources. A regular review of this data, typically using Centralized Monitoring elements, generates data signals to be interpreted regularly by the trial team. The team may identify where some risks may be increasing or becoming an issue. Trial teams can then respond to these data signals accordingly, considering the context of the data, and apply critical thinking to develop an appropriate response.
It is equally important to consider that there are often changes in a trial, such as protocol amendments. The trial team should review the protocol changes to understand if these have any impact on currently identified critical data and/or critical processes. This may trigger a review of current risk assessments and perhaps implementation of additional or revised risk controls to mitigate newly identified risks.
Traditionally, whilst risks have been reviewed and discussed during trials, it may not have always been given the attention and priority it deserves, as risk review is commonly an agenda item on regular project status calls. At Cmed, our experts utilize stand-alone risk review meetings, to ensure risk review and management is at the forefront of trial management. This ensures that risk review is not just an agenda item on a regular meeting where it may not be covered, or not covered in enough detail to be valuable.
How do these critical sections start to come together? Essentially, RBQM is not asking the industry to do something radical. It’s simply aligning tasks we are already well-versed in with what is most critical for a study. We can then mitigate higher risks to patient safety and data integrity and reliability in a proportionate manner, utilizing a structured cross-functional framework with robust documentation.
Below is an example of how Sections 5.0.1 through to 5.0.6 come together when evaluating a critical data point:
|Primary Objective||Overall Response|
|Is this Critical data? (5.0.1)||Yes – it supports primary objective (efficacy)|
|How will the data be collected / measured?||PET-CT Scans – collected locally; will be reviewed by PI. Result to be entered by site staff into EDC.|
|Is this a Critical Process? (5.0.1)||Yes – The scans must be taken as per protocol with the correct specification of equipment by a qualified staff member, and reviewed in a timely manner|
|What is the risk?
Risk Statement (5.0.2)
|If a site does not conduct the PET-CT Scan in accordance with the protocol, then this may result in missing data, which could result in an inadequate amount of data for the efficacy assessments|
|Risk Score (5.0.3)||3 (Likelihood=1, Impact=3, Detectability=1)|
|Should a risk control be applied?||Yes – impact is scored 3; the FDA recommends that all risks with a high score for impact must have a risk control applied|
|How will we control the risk?
Risk Controls (5.0.4)
|How will the risk controls be communicated to the project team?
Risk Communication (5.0.5)
|Periodic Risk Review Meetings
Risk Review (5.0.6)
|During the risk review meeting, the cross-functional team discusses this risk. The Clinical Trial Lead raises that there is an increase in missing end points relating to PET-CT scans upon review of the KRIs. In addition, the Lead Data Manager has reported an increase in automatic queries relating to missing scan data, and a backlog of manual data reviews regarding scans as the data is not present for this site.
Subsequently, the risk controls are yielding signals that need to be evaluated by the team, in context to the overall operational plans for the trial. This cyclical evaluation is best represented as:
In summary, whilst the industry may be more comfortable with the initial risk assessment part of the RBQM process (Sections 5.0.1 – 5.0.4), its value lies in the:
At Cmed, our team of experts, with 20+ years of experience of working on complex clinical trials for both biotech and pharm alike, focus on those things that truly matter with the goal being high quality clinical trial execution and outcomes. Implementing RBQM with the right proactive partner can increase communication and introduce active ways to monitor and manage trial risks in a dynamic, transparent fashion, thus saving valuable time and allowing you to achieve your milestones while confidently delivering regulatory authorities the evidence they require.
Get in touch with us today to discuss how Cmed’s RBQM team of experts can improve your next trial. Email us at: firstname.lastname@example.org