ICH E6(R3) and Retrospective Analysis: Taking RBQM Back to the Future

The team at Cyntegrity, a leading risk-based quality management (RBQM) innovator, engaged in a fireside chat on “How Retrospective Analysis Takes RBQM Back to the Future” during Halloran’s 2021 CORE event (Clinical Operations Retreat for Executives) in Chatham, Massachusetts. Their topic garnered attention from the attendees, especially with the impending regulations that will impact this clinical trial approach in 2022 and beyond.

As we settle in from the retreat and reflect on the insights shared, here’s an insider’s look at what was shared and why it’s important to take note.

What Is RBQM?

Risk-Based Quality Management (RBQM), in the simplest terms, is a mindset. It’s a consultative approach in which the organization builds into clinical trials the potential for likely risks, continually monitors for risk signals, and mitigates risk potential before it undermines data integrity, patient rights or patient safety.

As part of this approach, clinical research teams must leverage their historical knowledge from previous trials to inform future trials to assess what worked, what didn’t, how the therapeutic area, patient population, geographic regions, and trial design impact risk not only upfront but at every step along the trial journey. RBQM requires excellent data stewardship and a cross-functional understanding of critical data and critical processes and how they impact the trial.

We generally think about risk management in terms of cost and enrollment, but this is a new level. Ultimately, risk-based quality management provides information to guide conversations and decision-making and define who will act when risk materializes.

We’ve been hearing a lot about artificial intelligence and machine learning (AI and ML) this year – and at the retreat as well – and both technologies underlie the ability of RBQM to manage large amounts of data from multiple sources. RBQM leverages historical data across hundreds of trials to model predictive scenarios and categorizes risk by the severity of impact using these platforms. All of this information can be found and summarized in The Journal for Clinical Studies, Volume 13, Issue 3: “Prevention is Key: Shifting the Mindset to RBQM.”

But going risk-based requires lots of education upfront. So much so that many organizations have been reluctant to make this shift, even though our industry has been whispering and often shouting about this need for years. But through targeted education championed by clinical research teams, organizations have the potential to embrace the implementation process and contribute to its success, ensuring their organization’s RBQM strategy has the components it needs to meet regulatory expectations and live up to the internal expectations.

Now, this brings us to the upcoming guidelines our industry is required to meet. Take a breath – we’re in this together.

ICH E6(R3) Guidelines and The Future of RBQM

The International Council for Harmonisation (ICH) is committed to developing technical requirements for pharmaceuticals for human use in a manner that is responsive to the global community’s needs. The council’s Good Clinical Practice (GCP) guidance document – E6 – is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials involving human subjects’ participation.

The concept of what the latest published version of E6 (Revision 2 (R2)) attempted was trying to embed within our industry a different way of thinking – a risk-based mindset – asking researchers to implement a quality management system utilizing a risk-based approach. Even E6(R2) left ambiguities that undermine the very advantages of adopting risk-based monitoring; for example, the revision requires researchers to develop a systematic, prioritized, risk-based approach to monitoring clinical trials, but without much guidance on the process. As a result, many organizations have been resistant due to a lack of clarity.

Now we have a revision in the works that will be released shortly. It’s not simply an ask – it’s a requirement. When complete later this year, the third revision to E6 (R3) will contain twelve principles similar to E6(R2); however, it condenses to specific points that the ICH will release separately in two parts. And this new revision gives us an opportunity to lean in as an industry, think differently about clinical trials, and change how we think about trial execution.

Start by Educating First Through Retrospective Analysis

Clinical teams often ask, ‘where do we begin with RBQM?’ Transitioning to a risk-based quality management approach is met with much resistance, and to move through that phase as a team requires two essential components. The first component is change management, which is the people side of risk-based quality implementation, and the second component is project management, which is the process and technology side of implementation. It’s often underestimated what change management truly entails – and it truly is the people, process, and technology.

To kickstart RBQM, clinical teams preferably will need to conduct a retrospective analysis of a completed study to screen for pain points that highlight risk factors and critical processes to build preliminary risk history, or in other words, metric results and lessons learned. The findings will be your Proof of Concept (POC) when it’s time to find champions to bring along with you when you need to enact change and when you are tasked to convince senior management about the benefits of an RBQM implementation.

Your POC Question Guide:

• What risks manifested themselves during the study?
• When would it have been possible to identify these risky situations?
• At which point in time could they have been counteracted?
• Which risk defense strategy suits this study?
• How could this information be best used in the future?
• Which dynamics could be expected for similar studies?

Enable the Change Curve with Lots of Information

Education is key to overcoming the initial resistance barrier with your team members and management.

With any significant operational change, some in an organization will experience denial and resistance. That is just a fact. To move through that phase together, your team will need to communicate the right levels in the right way.

Here are six components to “right levels in the right way” broken down:

• As a leader, dive right “into the trenches” with your team
• Tailor the message so that each group is receptive in a way that will resonate with them
• Sell the new approach as superior to the old and communicate the value
• Focus on the data
• Do not do a big roll-out, but instead, pick out early adopters and turn them into change champions and advocates
• Repeat messages and be consistent

The Phased Program Approach

After developing your POC and beginning to transfer knowledge to all members of your team, you’ll need to focus on implementation. Such initial steps require all functions to be involved in clinical study conduct, such as Site Monitoring, Central Monitoring, Study Management, Project Management, Biostatistics, Data Management, IT, Pharmacovigilance, and potentially Drug Supply, Pharmacokinetics, and Bioanalytics, to generate a comprehensive list of potential risks in their respective areas.

Secondly, the risks need to be scored for their impact, probability, and detectability. In most cases, the risks with the highest scores are those then implemented in a risk-oriented study. Study teams subsequently identify and implement the so-called Key Risk Indicators (KRIs) based on metrics and respective thresholds. Those KRIs are usually based on data from various systems, such as EDC, ePRO, Clinical Trial Management Systems, Clinical Database Management System, Central Labs, Central ECG database, Pharmacovigilance/Drug Safety System Database, and PK databases.

The most straightforward approach to RBQM is the implementation of a library of common risks and their associated KRIs. Such an approach helps to avoid reinventing the already known risks over and over again. Such standard(ized), self-learning risk libraries can be consistently expanded by additional risks associated with a particular study.    

But organizations can’t often implement everything at the same time, so start with selective adoption. Try and adjust concepts on a small number of studies and embrace the process with early adopters. And then pull through the rest of the studies as those in the organization become more familiar and aligned as a team.

Lastly, if all goes well, the organization will begin the full adoption component by implementing the best pieces of experience on the whole portfolio of studies. This phased program approach will result in fully embracing the ‘new normal.’ As a result, organizations will reach full compliance and predictable study execution. What a future ahead of us, finally.

About Cyntegrity

Cyntegrity comprises an expert team of RBQM pioneers who want nothing more than satisfied clients and rewarding projects. Their collective focus on risk-based quality management has led their organization to prioritize regulatory compliance, where patient safety and data quality are central, over finding ways to reduce costs. Cyntegrity is a holistic RBQM solution provider with independent specialists supporting their compliant technology and processes to bring all risks and stakeholders in scope from start to finish.

About Halloran and CORE

Halloran is a full-service boutique life science consulting firm with offerings across strategy and program leadership, regulatory, clinical, and quality practices. Halloran partners with the most cutting-edge life sciences companies to enrich their product development and business growth through their expansive industry knowledge. From early development to commercialization, their flexible and integrated services are tailored to providing the know-how and a team of cross functional subject matter experts to propel organizations further. Because of their commitment to their clients and their patients, clients choose Halloran time and time again.

The Clinical Operations Retreat for Executives (CORE) was launched in 2004 – an invitation-only meeting that brings together an exclusive group of senior leaders in clinical development to discuss and debate the most pressing issues around the business of product development and building enduring companies in this space. This conference is a one-of-a-kind peer roundtable where executives learn from each other and share best practices. CORE is hosted by Halloran Consulting Group and founded by Laurie Halloran.