Establishing a Foundation for a Holistic RBQM Strategy by eClinical Solutions

How Risk-Aware Are You? Establishing a Foundation for a Holistic RBQM Strategy

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What’s Inside Understanding Risk-Based Quality Management .................................................................................................................... 4 How Does RBQM Differ from RBM? ............................................................................................................................................... 4 Current State of RBQM Adoption in the Market ................................................................................................................... 4 Drivers for RBQM Adoption Across Clinical Trials ................................................................................................................. 4 Key Elements of a Risk-Based Approach ....................................................................................................................................... 5 Taking a Proactive Approach to RBQM Adoption ...................................................................................................................... 7 Getting Ahead of Adoption Challenges ......................................................................................................................................... 7 Applying a Holistic RBQM Strategy .................................................................................................................................................. 7 Implementing Risk-Based Quality Management ....................................................................................................................... 9 Establishing a Foundation for Digitial Clinical Trials with elluminate® ................................................................. 9 Learn More ................................................................................................................................................................................................................... 10

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White Paper — Establishing a Foundation for a Holistic RBQM Strategy

Introduction Ensuring patient safety is a critical objective across all clinical studies. To keep participants safe, while keeping clinical trials on track, proactive monitoring and early detection of potential risk play key roles in the drug development process. Initial guidance from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for adopting a risk-based approach to clinical trial monitoring was released almost 10 years ago. The FDA and EMA continue to press the industry to meet the guidance objectives. This guidance, in addition to continuous updates to The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) standards around total quality management objectives, have caused risk-based monitoring (RBM) to become a more common practice across all clinical trials. In recent years, the adoption of decentralized trial (DCT) models has created both opportunities and challenges in clinical development. While DCT models make trials more accessible and relieves patient burden, the volume and variety of study data collected adds greater complexity to trial management and monitoring processes. One strategy to address the increasing complexity of trial monitoring is to evolve from RBM to Risk-based Quality Management (RBQM) — which is an end-to-end process that begins with protocol design and focuses on factors critical to quality throughout the trial lifecycle. This paper will highlight why the industry is moving towards RBQM and how sponsors can build a scalable approach that protects trial participants, upholds study integrity, and increases operational efficiencies.

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Understanding Risk-Based Quality Management How Does RBQM Differ from RBM? Risk-based monitoring (RBM) and Risk-based quality management (RBQM) share a similar focus on identifying and mitigating potential risks. Where RBM and RBQM differ is in how widely they are applied in a trial. RBM is a piece of an overarching RBQM strategy and while RBM uses advancements in technology and analytics to track and predict risks, RBQM is a more expansive process. Focusing on factors critical to trial quality, RBQM begins at the time of protocol design — so that mitigation can be built into the protocol and other trial documents — and identifies risk on an ongoing basis for the duration of the trial. In today’s evolving clinical trial landscape, a clinical trial often includes millions of data points, making RBQM more essential than ever before. When sponsors leverage this end-to-end methodology, trial participant risk is reduced and costly down stream issues are avoided.

Current State of RBQM Adoption in the Market Over the last two years, the life sciences industry has seen a dramatic acceleration in digitization and technology adoption, especially in clinical development. The industry has embraced numerous technical capabilities such as decentralized trial platforms and risk-based quality management solutions that had been “emerging” for many years and are now becoming mainstream. The Gartner 2021 Hype Cycle for Life Science Research & Development — which explores areas of innovation that will enable life sciences organizations to respond to industry challenges — recently highlighted this trend. In this report, risk-based and central monitoring approaches were classified as “on the Slope of Enlightenment.” 1 This classification indicates that over the next two to five years, the implementation and expansion of RBQM practices by sponsors will gain increasing momentum as digital transformation continues, driving the need for more advanced RBQM technology and strategies to support innovation and the adoption of these approaches.

Drivers for RBQM Adoption Across Clinical Trials While RBM adoption within the drug development industry has been on the rise for years, regulatory and external factors are driving life sciences organizations to take it a step further and evolve from RBM to RBQM in order to meet the demands of more adaptive and digital clinical trials. Risk-based monitoring started to gain traction in 2013 when the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) released guidance for adopting risk-based approaches for more efficient trial monitoring.2,3 In 2016, The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) released ICH E6 (R2), requiring sponsors to develop risk-based methods to assess and manage trial risk.4 Following that, the FDA placed ICH E6 (R2) as a revision to Good Clinical Practice (GCP) in the federal registry. The third revision to ICH E6 is expected in 2022 and will focus on risk-based approaches and the concept of quality by design while acknowledging the diversity of trial design, data sources, and different contexts in which clinical trials can be conducted. Additionally, RBM guidance and approach documents released by pre-competitive alliances such as TransCelerate BioPharma have helped to further drive the adoption of risk-based approaches.

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The Covid-19 pandemic has been an undeniable force in bringing sweeping changes to the way clinical research is conducted. Most significantly, the pandemic has been a catalyst for moving away from inefficient practices and pushing new clinical trial execution models to become standard practice. With remote and virtual monitoring approaches becoming mainstream, many organizations were forced to prioritize risk-based approaches, further accelerating the initiatives set in motion by ICH E6 (R2). The pandemic has proved that the drug development industry can no longer rely on inefficient trial execution models and must instead pivot to approaches that prioritize proactive risk assessment and mitigation.

Related Resource: Risk-based Approaches for Active Oversight & Improved Monitoring

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Furthermore, these drivers for adoption are impacting both insourced and outsourced trial models. Emerging and mid-size sponsors working in outsourced models are adopting RBQM at an increasing rate. Using RBQM technology and methodology in an outsourced model enables sponsors to take a data-driven approach to overall risk assessment and analysis, creating additional value to supplement a CRO’s oversight strategy.

Key Elements of a Risk-Based Approach There are several important elements of an RBQM solution and depending on the complexity of the trial or analysis required, all or some of these elements can be incorporated into an RBQM strategy. Methods of implementing these components vary and are contingent to the technology infrastructure within an organization.

• Risk Assessment and Categorization Tool (RACT): Risk assessment is a key component of risk

management and is performed to identify potential risks impacting critical data and clinical trial processes. There are a few industry-specific risk assessment methodologies that can be utilized to perform a risk assessment such as the Transcelerate framework. With a Risk Assessment and Categorization Tool (RACT) that leverages a methodology similar to Transcelerate, it can be used to manage a library of risk assessment questions and maintain study-specific questions. A RACT can often be tailored to the protocol to ensure the appropriate questions are asked in order to best identify and assess study risk.

• Key Risk Indicators (KRIs): Key Risk Indicators (KRIs) are metrics used to monitor identified risk throughout the duration of a trial, allowing for quicker detection and mitigation of potential issues. The number and type of KRIs selected depends on the protocol and complexity of the trial. KRIs are most effective and accurate when there is robust, real-time study data to feed these measurements.

• Quality Tolerance Limits (QTLs): Quality Tolerance Limits (QTLs) are pre-determined limits for specific trial parameters that signal possible risk or further investigation when reached. Unlike KRI’s which are used to identify issues at the site performance level, QTLs are utilized to detect systemic deviations across a study. However, both KRIs and QTLs enable monitors to prioritize where to take immediate action.

• Centralized Statistical Monitoring (CSM): With Centralized Statistical Monitoring (CSM), aggregated

electronic clinical trial data can be reviewed remotely, eliminating the need for on-site monitoring. The value of CSM became even more apparent when on-site monitoring was not possible during the pandemic, leading to significant trial disruptions across the industry. With CSM, statistical algorithms can be applied to the aggregated trial data to enable the detection of anomalies and differentiate areas of concern with statistical significance.

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The methods by which some or all of these RBQM components are incorporated into a monitoring strategy has evolved over the years. Prior to the availability of RBQM point solutions, RACT, KRIs, and QTLs were primarily managed in spreadsheets or manual trackers. With point solutions, those components can be managed from a single system that also enables CSM. And while an RBQM point solution undoubtedly improves trial efficiency, taking a platform approach to RBQM provides access to all study data in real-time, enabling greater accuracy, advanced analytics, and better oversight.

Streamlined end-to-end clinical data workflow

Increased Value

Built-in workflow engine, issue integration, & action automation Access to Clinical Data Repository (CDR) & Operational Data Repository (ODR) CSM

CSM

RACT KRIs QTLs

Excel/Manual

RBQM Point Solution

RBQM within a Clinical Data Platform

Modern Technology & Advanced Capabilities

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Taking a Proactive Approach to RBQM Adoption Getting Ahead of Adoption Challenges An environment of disparate clinical data, fragmented technology, and siloed resources are all barriers to adopting RBQM successfully.

• Disparate Clinical Data: Some of the challenges with RBQM adoption are due in part to a chaotic data

environment. Though more data types and sources have created a richness in data sets that have benefited clinical research, they have also contributed to data chaos. Oftentimes, various data types and sources are stored in disparate systems, resulting in data variability, manual processes, and disjointed workflows between clinical teams. With system and data chaos, there has been a reluctance to adopt RBM / RBQM solutions as they have historically been considered yet another system to manage.

• Fragmented Technology: Another RBQM adoption challenge is rooted in technology. For an RBQM

application to effectively assess and mitigate risk, it relies on a robust data pipeline to do so. RBQM as a point solution requires significant and oftentimes manual work by clinical teams in order to export, assemble, and then integrate disparate data sources within the solution. These inefficient, manual processes increase room for error and do not allow for a real time, holistic view of the data. Without accurate data that is being continuously refreshed, an RBQM application is less effective, leading to incomplete, non-contemporaneous data insights and delayed risk assessments, causing trial rework, delays, and potential risk to participants.

• Siloed Resources: Additionally, clinical teams that support risk-based quality management — typically

data management and central monitoring teams — are often siloed. With organizational silos, clinical teams are often working in different systems to perform data mining, statistical analysis, and other due diligence required for RBQM. As a result, the probability of manual error increases and trial timelines are hindered.

To address and overcome these challenges, sponsors must take a holistic approach to RBQM with an integrated, comprehensive technology solution.

Applying a Holistic RBQM Strategy Taking a holistic approach to RBQM adoption — understanding how technology, processes and people are key parts of the overall strategy — positions life sciences organizations for more efficient monitoring and improved outcomes while complying with regulatory recommendations.

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Technology

Process

People

When developing an RBQM strategy, these components are essential considerations:

• Modern Technology: Moving at “the speed of science” means

How To: Mitigate Risk with a

having clinical data available in near-real time to make decisions with Platform Approach to confidence and accuracy — leveraging modern technology is essential RBQM in order to move at this pace. Rather than working in multiple systems Watch Now to manage and monitor clinical data, a future-forward clinical data platform provides a single source of truth where all data can be collected and reviewed in near real-time. A modern platform not only reduces manual efforts, optimizes resources, and enhances productivity throughout the clinical trial lifecycle, but it provides a data-rich environment necessary for efficient risk assessment and identification. A data-rich environment feeds Key Risk Indicators (KRIs) to provide comprehensive risk profiles and a more holistic view of risk, enabling a data-driven monitoring effort and active oversight. Additionally, this complete view across all study data provides better visibility into the status of the study for all stakeholders across an organization.

• Automation & Process Optimization: Once all study data is integrated into a centralized location such as a clinical data platform, risk can be identified and assessed on an ongoing basis. To address risks efficiently, an ideal RBQM solution includes the ability to automate recommended actions based on risk-level or as threshold limits are being reached. Automated actions within a single system creates a seamless workflow across clinical teams, ensuring appropriate quality oversight throughout the duration of a clinical trial.

• Cross-functional Collaboration: Depending on the size of a life science organization, the traditional

data management, clinical monitoring, and data science roles are often converged. This intersection of clinical functions creates an even greater imperative for adopting an RBQM solution within a clinical data platform. When RBQM is part of a unified platform, all teams are working off the same data management workbench, strengthening communication and collaboration. Added value can be found within RBQM solutions that serve as advanced data management workbenches with access to advanced statistical methods and visualization capabilities that enable roles across clinical teams to support oversight efforts.

ERATIONAL DA OP TA

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CL IN IC A

REPOSITORY TA DA

Breaking silos with integrated workflows and interoperability

ORY SIT O EP

Combined CDR, ODR and MDR enables use cases across the clinical development value chain

Automation and standardization at scale to unlock value

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Implementing a Risk-Based Approach As innovation in clinical development accelerates and more data than ever is being created from an expanding set of sources — from wearables to genomics — the complexity of clinical data and metadata management — and the impact of RBQM on trial monitoring practices — will continue to increase. Regardless of how much the industry evolves, ensuring study integrity and patient safety will remain core priorities in clinical research. Leveraging the right technology will not only ensure that these objectives are achieved but will also provide an opportunity to streamline processes and increase operational efficiencies across clinical teams.

elluminate RBQM in Action Watch Now

Establishing a Foundation for Digital Clinial Trials with elluminate The elluminate Clinical Data Cloud serves as a foundation for digital trials, providing a centralized location for all your clinical and operational data, regardless of source. As part of the elluminate Clinical Data Cloud, elluminate RBQM is designed to enhance your data management and monitoring strategy and adds to the breadth of the integrated products within the elluminate platform. By taking a platform approach, analytics silos are removed and the need to access multiple applications for high-quality data is eliminated.

One platform for clinical and operational data from ingestion to insights—across all data sources

DATA INGESTION, MAPPING & STORAGE

DATA SOURCES

INTELLIGENT APPLICATIONS

DATA CONSUMERS

Genomics Labs EDC

EHR eSource

MDR eCOA

Data Management

Mapper

Data Central Medical Monitors

Claims

CTMS Insights

CTMS IVRS

Importer

Analytics

Clinical Operations Biostatistics

FORMATS

RBQM

Excel

Metadata & Standards CSV

Statistical Computing Environment

MDR CDR ODR

Executive Management

One platform for clinical and operational data from ingestion to insights -across all data sources

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White Paper — Establishing a Foundation for a Holistic RBQM Strategy

Having access to a centralized, data-rich environment like the elluminate Clinical Data Cloud as a foundation for RBQM provides a holistic view of risk — resulting in more efficient and accurate monitoring practices. With built-in actions and a powerful role-based workflow engine, issues are centralized within the platform, creating a seamless workflow between Data Management, Central Monitoring, and Clinical Operations teams and facilitates the identification of potential issues the moment they arise — ensuring patient safety and data integrity throughout a trial. For trials requiring more advanced risk monitoring whether due to data variability or other external factors, elluminate RBQM provides Centralized Statistical Monitoring (CSM) capabilities for advanced statistical analysis. With CSM, areas of concern and non-significant changes in study data can be differentiated with statistical significance. Additionally, elluminate RBQM serves as an advanced data management workbench, diminishing silos within clinical teams to support greater cross-functional collaboration. With out-of-the-box access to advanced statistical methods and data-driven review techniques, tiered data review and cross-functional data validation is performed from a single location, enabling faster time to insights.

Learn more The demands of modern clinical trials can be met by taking a platform approach to enable a comprehensive RBQM strategy. eClinical Solutions’ products and services are helping life sciences companies adopt a more modern data infrastructure to break down data silos, automate manual processes and accelerate the speed of drug development. With the elluminate Clinical Data Cloud, life sciences organizations can begin to maximize the value of their clinical data, help their teams accelerate development processes, and serve patients more efficiently throughout the clinical trial lifecycle. For more information or to request a demonstration of elluminate RBQM, visit us at https://www.eclinicalsol.com/products/risk-based-quality-management or email us at info@eclinicalsol.com

References 1 Gartner, Hype Cycle for Life Science Research and Development, 2021, 19 July 2021, By Jeff Smith, Michael Shanler 2 The Food and Drug Administration, Industry on Oversight of Clinical Investigations - A Risk-Based Approach to Monitoring, August 2013 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oversight-clinical-investigations-risk-basedapproach-monitoring 3 European Medicines Agency, Reflection Paper on Risk Based Quality Management in Clinical Trials, November 2013 https://www.ema. europa.eu/en/documents/scientific-guideline/reflection-paper-risk-based-quality-management-clinical-trials_en.pdf 4 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice, November 2016 https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf

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