Johann Proeve, PhD

	Even though the ICH GCP E6 R2 guideline had been released quite some time ago, companies still struggle with “taking a risk-based approach” to monitoring and quality management. The implementation of the commonly perceived “abstract” guideline seems challenged by the lack of practical experience and knowledge helping those supposed to convert the requirements into a day-to-day routine move forward more quickly.

	Originally, everybody was under the impression that this guideline is mainly looking into risk-based monitoring (RBM), i.e., a process to reduce source data verification and, as a result, save on monitoring resources while, in turn, not jeopardizing the quality of the data. Rapidly, it became clear that this understanding would mean to jump too short. For that reason, the term risk-based quality management (RBQM) had been introduced, moving away from the unilateral view of just monitoring. 

	RBQM starts already at the development level of the target project profile, and subsequently covers the development of the protocol, the electronic case report form (eCRF), the data structure, the decision on the inclusion and exclusion criteria to be applied, the processes around the data capture topic (EDC, ePRO, wearables, central lab, central ECG, biomarkers, PK data, etc.), the enrollment, the data entry, the response to queries, the quality of the data generated, and eventually also the processes around the data traveling through the many systems. For example, from source to EDC, to the backend data management system, partially into the CTMS, safety data into the pharmacovigilance or safety database and eventually into the CDISC SDTM and ADaM database structure.

	In real life, study teams, stakeholders, and leadership first have to understand the concept, the rationale, and the background of the updated ICH guideline before they feel confident enough to embrace the RBQM process integration and are able to contribute to its success. 

	As a consequence, Cyntegrity regularly gets approached by its clients with the request to provide education on RBQM process integration, addressing both the basic and more advanced aspects of it. About nine months ago, Cyntegrity was contacted by Merz Pharma with a similar request for professional education. Based on the current, revised regulatory view, Cyntegrity offered Merz a four-layer certification program, i.e., the MyRBQM Academy White, Green, Black, and Executive Belt curricula, and a real-life case study workshop that involved the retrospective analysis of an already completed trial.

	The White Belt course-the fundamental knowledge:

	In order to make this fundamental RBQM knowledge level accessible to a broad clinical research audience, Cyntegrity decided to create a compact online course. The beauty of such a format is that everybody can run the training self-paced at any time when it is convenient. Importantly, such basic training on RBQM is relevant to almost everyone involved in the clinical trial arena and  beyond.

	The online White Belt certification covered the main aspects of the ICH E6 R2 guideline, as well as the latest ICH E8 draft, and provided real-life examples using engaging ask-the-expert style video clips. 

	This first belt level was received very positively by Merz’s e-course participants, i.e., all staff completed the course within the expected timeframe. At the end of each course chapter, participants had to complete a multiple-choice quiz. Fortunately, all participants managed to successfully complete the quiz at the end of their White Belt online course. This was important since the successful completion of the White Belt course was the prerequisite to attending the subsequent belt levels. 

	The Green Belt course-when could we have known analysis:

	This course was set up differently from the White Belt course. Since RBQM is a functionally overarching exercise, representatives from various functions were invited to this instructor-led training. 

	In preparation for the Green Belt course, Cyntegrity reviewed a sponsor protocol of a completed study, identified the potential risks, determined the key risk indicators (KRIs) and linked them to the risks. In addition, Cyntegrity had access to the data from a completed study and analyzed the data available with respect to their contribution of the study failure. The question to be answered was, if the implementation of RBQM prior to the start of the study would have facilitated an early detection of the factors driving the study failure.

	The sponsor company had been asked to also come prepared to the instructor-led workshop, so that the risks the sponsor identified could be compared with those risks determined by Cyntegrity. Comparing the two sets of risks and risk indicators revealed quickly a rather high congruence of the two sets. That means that even a team that had not been exposed to RBQM a lot faster can learn what is important and what is less important to look at.

	Based on this and many other similar exercises, Cyntegrity developed a list of “gold-standard” KRIs, i.e., a set of KRIs that are applicable to most of the clinical studies at Merz and even industry-wide. These KRIs included the enrollment over time and the adverse events/serious adverse events reporting.

	After identification of the risks and the analysis of the respective data, the workshop participants looked at the development of the risks over time. That means for example, looking for a point in time when a particular site in the study, or several sites, started deviating from the expected pattern. Of course, this requires that the underlying system permits a rather tight screening of this data, meaning that the system must run quite frequently across the respective data. 

	It turned out that the system-had it been implemented-would have alerted the study project manager earlier on on the factors contributing to the study to fail. The sponsor company-like several others we provided training for-had also identified those risks in their studies, however, usually too late to act upon them in a timely fashion and with a lot of manual effort. 

	This hands-on workshop was perceived very beneficial to those closely involved in the rollout of RBQM, as well as those supposed to manage the system once the rollout had been completed. As many recognize, implementation of a new system in an organization requires a significant amount of preparatory work and is associated with change management, something Cyntegrity covered in the Black Belt course.

	Black Belt course-continuous optimization:

	Increasingly, pharma, biotech, and medical device companies, as well as clinical research organizations, are observing that their programs concerning the use of new technology are not achieving their intended outcomes. In particular, compliance programs are seen as too expensive, ineffective, and unable to keep up with the new and emerging ICH GCP standards and regulations. Compliance appears to be falling behind and exposing biopharma companies to unnecessary risk.

	So, when planning and implementing improvements to their research operations-whether that means creating new processes to ensure regulatory compliance or adopting a new piece of technology-it is essential that they’re not forgetting the basic principles of change management. The most difficult part of any initiative is the behavior change it calls for, and RBQM is no exception. The implementation of RBQM without an implementation strategy is just a wish.

	Cyntegrity developed the Black Belt course mainly to address the change management aspect when working on a RBQM rollout. The course had been created for a subgroup of those people that already passed the White and Green Belt courses successfully, and is intended for those in charge of a rollout of the processes and tools into the organization. It addresses the main aspects of change management, the various reactions usually surfacing in the staff's mind when a change shows up on the horizon and how to address their concerns in a way that they support the change eventually.

	In addition, the Black Belt course offered the opportunity to address specific questions and situations related to the implementation of RBQM in the respective organization, which might be different from case to case.

	All of the completed educational journeys certainly lived up to Merz’s expectation with respect to a successful introduction to the RBQM topic, facilitating a sound understanding of the challenges and opportunities associated with RBQM, and even addressing the change management topic. 

	However, new processes and new technology linked with an initial investment also require the buy-in of leadership. To that end, Cyntegrity also developed a concise Executive Belt level.

	Executive ‘Gold’ Belt course-calculate your ROI:

	Other than the first three belt levels, the Executive Belt course especially focuses on the key performance indicators of the RBQM implementation, so that leadership fully understands the requirements by the health authorities and the benefits for their own organization. Using real-world evidence-as explained for the Green Belt course-helped a lot to highlight the importance and the benefits of RBQM.

	In addition to the Green Belt case study analysis, Cyntegrity developed an RBQM ROI calculator supporting the calculation of the “return on investment” performance measure and the benefits of RBQM permitting the user to enter their specific underlying data and calculating their resulting ROI. 

	Turning the abstract concept of RBQM into practical routines remains challenging for most biopharma companies. Overall, the implementation of RBQM requires a solid preparation. The provision of a set of training modules helped the organization-in this case study, Merz Pharmaceuticals-to initiate a smooth RBQM rollout. Based on the feedback of Merz and other clients, such an educational approach would also help others to jump onto this bandwagon and be successful in the RBQM arena.

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