Clinical trials, however, continue to be difficult and expensive to manage. Yet successful clinical trials, however, remain critical for investors. Small biopharmas are thus looking for guidance in navigating clinical trial design to limit risk and bolster their chance of success.
To help identify what emerging biopharma companies need to know to keep in mind when planning clinical trials, we reached out to two experts at IQVIA. Adrian Kizewski is an associate director of RBQM, digital trial management suite at IQVIA, while Gayle Hamilton is a director in the same division at the company.
What is the difference between Risk-Based Monitoring (RBM) and Risk-Based Quality Management (RBQM)?
Adrian Kizewski: Risk-based monitoring is the process of ensuring the quality of clinical trials by identifying, assessing, monitoring, and mitigating the risks that could affect the quality or safety of a study (protocol-based). Risk-Based Quality Management is applying risk-based monitoring at a systematic level for managing quality throughout a clinical trial. A proven approach is to leverage the “PODAR” process that is driving the way we are developing our RBQM technology – Plan | Operationalize | Detect | Action | Retrospect.
- Plan: Identify critical risks, mitigation strategies, and roles & responsibilities; Finalize through a cross-functional review and approval
- Operationalize: Define clearly how mitigation strategies will be operationalized utilizing operational plans assigned to the respective stakeholders or roles performing the activities
- Detect: Surface algorithm-driven automated alerts with embedded AI/ML insights focused on the past, present, and future leveraging real-time access to data
- Action: Manage automated and manual alerts driven by SOP-like workflows enabling issue management, communication pathways, exploratory analytics, oversight, traceability, and auditability
- Retrospect: Reflect and revise the approach by conducting an ongoing risk assessment enabling the team to adjust in real-time as they monitor the trial, sites, and subjects
How can RBM and RBQM assist with regulatory compliance?
Gayle Hamilton: RBQM became part of regulatory requirements effective with ICH E6(R2) published in March 2018. The regulations are designed to support better design, quality, and subject safety, which in turn should support better compliance. Currently, there are many studies being conducted where only partial processes are in place due to the lack of knowledge, understanding, technological capabilities, and a burdening resistance to adopting RBQM due to disbelief in the process compared to how the industry has been conducting monitoring since its inception.
When should companies prioritize one versus the other?
Kizewski: Our experience shows it’s not a one vs. the other situation from a regulatory standpoint, however, many companies implement the risk-based approach in a stepwise fashion based on resources and technical ability. Certain processes are expected to be conducted despite technological capabilities.
Many companies start with documentation of RBM identified risks in a word or excel format. The natural transition is to then utilize a system to document and track risks and perform monitoring through the same system with bilateral integration of the systems- where data feeds from the risks to the monitoring and back. Automation of reports and alerting would further support the trial being run in a systematic RBQM fashion.
Are RBM and RBQM complicated and time-consuming to implement?
Hamilton: The complexity and amount of time to implement are process and system dependent. When manual processes are utilized to implement a risk-based approach, the amount of time it takes to complete a task can be extraordinary.
Newer SaaS-based RBQM solutions are designed to be flexible enough for the stepwise implementation of RBQM or full use despite the number of resources available. In smaller organizations where many resources wear multiple hats, the system would allow for a CRA to do both the expected CRA requirements and review site and subject data remotely. For large organizations, where resources are usually assigned single dedicated project team roles, the centralized monitoring is typically a separate role from the CRA.
Technology solutions also offer opportunities to enable the overall process more efficiently and effectively, creating a better uptake by the organization.
Processes such as risk planning are difficult to navigate in the initial stages of RBQM implementation. Our latest SaaS-based RBQM solution has built-in therapeutic area and indication level risk plan templates based on the last decade or more of IQVIA experience in RBM and RBQM. This reduces the workload and increases efficiencies by approximately 50%, and, in turn, improves quality and safety, which reduces the risk of not monitoring the correct data (and, of course, reduces audit findings!).
Other opportunities include leveraging intelligent system workflows to reduce the learning curve with a new system. It removes the crux of the issues with data literacy which is new to most project team members. In addition, it offers a systematic way to guide the team in managing risks & issues that reflects both company and industry guidance.
How can RBM and RBQM help sponsors manage high clinical trial complexity?
Kizewski: As quality is expected at the forefront of the protocol design, this begins the process of identifying and mitigating risks and trial complexities. The process can help to eliminate unnecessary assessments, and identify where data may be collected through uncomplicated Electronic Capture of Assessments (eCOA), thereby reducing the subject and site burden of additional subject visits with data being available remotely.
In traditional monitoring, many issues are often identified after a CRA has conducted several visits at a site which can be 6-9-12 months after the first patient randomized. The monitoring focus is on the documentation and Source Data Verification (SDV) checks rather than analyzing the broader site and subject data across the trial.
Leveraging a risk-based approach enables the identification of risks & issues earlier in the trial due to being able to review the data centrally in a near real-time process. This enables remediation to be implemented earlier and prevents further issues from occurring later in the trial (reduction in protocol deviations).
A simple example to illustrate the power of the process can be made with inclusion/exclusion criteria. Eligibility issues identified earlier in a risk-based model enable the project team to establish if there are complexities within the trial that will prevent endpoint analyses from being conducted. This is critical to the trial as it directly affects the ability to submit trial results to the regulatory authorities for the approval of the therapy. Identifying these issues earlier brings awareness and the ability to course correct so that the trial is not jeopardized.
What are the change management issues involved in implementing RBM or RBQM?
Hamilton: Depending on the maturity of the sponsor, we typically propose a tailored “walk – crawl – run” approach to preparing the organization for the shift they are about to undertake. This involves looking at it through the lens of people, process and technology.
From a people perspective, RBQM requires buy-in from the cross-functional team, which includes clinical operations, data management, medical monitoring, biostatistics, etc. Historically, we’ve lived in a technology world of point systems and solutions that have overburdened and siloed our cross-functional teams. RBQM brings these teams together to identify risk holistically across the trial and deploy a central process to monitor for and mitigate risks/issues. The collective buy-in is essential to deploying an effective RBQM strategy. In addition, the central monitoring role is new to most organizations. It is commonly implemented by upskilling existing staff, hiring new resources, divvying up responsibilities amongst existing staff, or outsourcing to a CRO.
From a process perspective, RBQM enables a shift from a reactive state to a proactive state that relies on processes and analytics to assess relative risk driving mitigating and preventative actions. The dynamics of the trial as a whole change because the focus shifts from looking at all data to the data that really matters. No longer is the CRA going on a cadenced visit every 6-8 weeks to perform 100% SDV. Much of the data is reviewed remotely, where possible, and issues and trends are identified before the CRA onsite visit. The CRA focus becomes more on the process the sites are following to obtain the data to ensure it’s being collected as per the protocol so that the endpoint analysis can compare the data more equivocally. The CRA is the relationship manager, monitoring data that can only be reviewed onsite and the most critical data, and focuses on the issues identified through remote monitoring. Processes as early as protocol design and as late as trial closeout are impacted by RBQM. The impact requires a sponsor to critically evaluate how to embed RBQM to realize the benefits and eliminate redundancies. We recommend that RBQM naïve sponsors take a stepwise approach to scaling up over time.
From a technology perspective, the technical solution must be designed to enable the RBQM process. The system should be integrated into the sponsor ecosystem to support the cross-functional teams and data that will be leveraged for the central monitoring reviews. It should facilitate an end-to-end risk planning process that can be operationalized (operational plans). The capabilities enabling planning should be integrated with the monitoring capabilities, including (but not limited to) the mechanisms for alerting to risks and the way monitors action them. The overall solution should enable RBQM to be applied to any trial in any phase, from traditional to fully decentralized.
What benefits will my organization see from using an RBM or RBQM approach?
Kizewski: The simple answer is reduced risk and cost, improved data quality, enhanced patient safety, and improved operational efficiency.
- Reduce risk and cost
- by implementing a continuous risk assessment to identify, document, plan, and mitigate study risks through a systematic end-to-end solution enabling you to deploy a monitoring strategy designed to optimize resources
- Improve data quality
- by performing reviews on clinical and operational data centrally to identify issues and effectively work towards resolutions in real-time
- Enhance patient safety
- through early signal detection of eligibility issues, safety, and medical incongruencies leveraging analytics with embedded AI/ML
- Improve operational efficiency
- through oversight supported by faster data flows and communication pathways to lower error rates, enabling site compliance & quality
The benefits are truly immeasurable!
Can you provide some context on how to scale nascent RBM or RBQM programs into more mature deployments?
Hamilton: Like our change management approach, we recommend looking at deployment decisions through an overall people, process and technology lens.
Key questions from a people perspective:
- Do you have the resources internally to deploy an effective RBQM solution?
- Do the resources have the required skill sets?
- Do you want to be responsible for the execution or just the oversight?
Working with CRO organizations can help quickly supplement organizational needs. Services can be as extensive as full execution or simple as staff augmentation. Models such as staff augmentation can support upskilling existing resources to meet the needs of RBQM to bring those capabilities in-house.
Key Questions from a process perspective:
- Do you have the experience in-house to develop RBQM processes?
Working with organizations that can provide advisory services from an experienced clinical operations perspective with respect to RBQM can quickly help fill in gaps in understanding and develop effective processes that complement and streamline the existing organizational processes. It is extremely important to embed RBQM across the clinical value stream from design to closeout to realize the full benefits. An advisory partner can help drive how much RBQM to implement and how fast the organization should scale up.
Key questions from a technology perspective:
- Do you want to own the technology?
- Will the technology solution be custom (i.e., built in-house) or purchased (i.e., from a vendor)?
Industry guidance specifies that the sponsor is ultimately responsible for managing risk in the trial regardless of the outsourcing model. We have been engaged with sponsors moving towards an outsourced model that requires the CRO to work in their RBQM technology. This enables the sponsor to maintain oversight of the activities being conducted and other efficiencies.
Sponsor experience, budget, and in-house capabilities will govern whether the solution will be built in-house or purchased from a vendor. When purchasing SaaS solutions, we recommend working with a product company with a proven track record. There are many different types of systems available, but not all are equal in their capabilities, and vendors have varying experience in running clinical trials with a risk-based approach. In addition, the solution should enable the end-to-end RBQM process that the organization defines.
Organizations like IQVIA can support across the people (resourcing), process (advisory services), and technology (SaaS RBQM solution) RBQM needs to leverage our experiences in pioneering the evolution of RBM to RBQM.
Filed Under: clinical trials, Drug Discovery