Director of Solution Services, Remarque Systems
Without clear-cut evidence that clinical trial results are reliable – and that treatments are both safe and effective - billions of dollars and years of hard work are rendered moot. Yet as trials grow in complexity, acquiring unequivocal proof becomes equally complex. Risk-Based Monitoring (RBM) grounded in Risk-Based Quality Management (RBQM) can streamline the process. Using these strategies, researchers proactively incorporate quality into study design rather than retroactively, and painstakingly, monitoring results.
Fortunately, the International Council for Harmonisation (ICH) recognizes the value of RBQM and RBM. The ICH sets international standards for both ethical and scientific quality; since 1996 its Guidelines for Good Clinical Practice (GCP) have steered the design, conduct, recording, and reporting of clinical trials. This industry-wide consistency underpins a well-structured drug-marketing application, a rapid and efficient regulatory review process, and a higher likelihood of first-cycle approval.
In 2016, ICH updated their GCP guidance. The revision, ICH E6(R2), asks researchers to implement a quality management system utilizing a risk-based approach. Yet researchers have been slow to act. The problem: lack of clarity concerning implementation of the guidelines.
Soon, this will change.
Risk-Based Monitoring Is A Recognized Industry Standard
The premise behind a risk-based approach is simple: Not all data, and not all actions, have an equal potential impact on study outcomes. Consequently, they do not deserve equal scrutiny. Rather than laboriously verifying the accuracy of every piece of information related to a study, researchers should identify, assess, control, and mitigate risk across study operations, safety, and quality measures. They can do this both simply and effectively by leveraging advanced technical capabilities, centralized monitoring, and statistical assessments. This will spotlight potential risks and guide highly targeted site monitoring visits.
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special offers
from Pharmaceutical Outsourcing – all delivered right to your inbox! Sign up now!
This strategy is broadly supported among industry organizations. In 2013, the Clinical Trials Transformation Initiative (CTTI) promoted Quality by Design (QbD) as a means of increasing the quality and efficiency of clinical trials. Further, in 2019 the U.S. Food and Drug Administration (FDA) together with the European Medicines Agency (EMA) stated that, “when good quality risk management and quality by design processes inform the development of RBM, its effective implementation can maximize study quality by focusing monitoring activities on processes and procedures critical for the protection of trial participants and managing data integrity.”1 ICH E6(R2) simply codified this industry trend.
Emphasizing the value of a systematic, prioritized, risk-based approach to monitoring clinical trials, ICH E6(R2) recommends that sponsors:
- Identify, during protocol development, data and processes critical to ensuring patient safety and the reliability of trial results, and the risks to such critical data and processes.
- Evaluate the likelihood, detectability, and impact of such risks.
- Determine if risks are acceptable or if they must be reduced based on prespecified limits.
- Document and report risks in the clinical investigation.
- Review risk control measures periodically, to ascertain effectiveness of risk-control measures and to take into account emerging knowledge and experience.
To support these recommendations, ICH E6(R2) states that the researcher may choose on-site monitoring, centralized monitoring, or a combination of the two. Today’s technologies simplify adherence.
New Technologies Support A Risk-Based Approach to Clinical Trial Design and Management
In order for a holistic RBQM framework to protect patient safety, data integrity, and regulatory compliance, it must:
- Be flexible enough to adapt to new knowledge gleaned from ongoing inputs.
- Clearly enumerate any potential critical issues, how they will be detected, and who is responsible for documentation, investigation, and follow-through.
- Identify critical to quality (CtQ) factors related to efficacy, patient safety, and data reliability.
- Assess, identify and mitigate risks that have the greatest impact on subject safety, data quality and integrity, and regulatory compliance.
- Capture and store all CtQ data, data interpretation, and any supporting actions.
In an RBQM scenario, researchers continuously monitor leading quality indicators and potential risks. They do not try to predict the future, nor do they only discover issues during retrospective data inspection; instead, they make informed choices based on real-time information throughout the study. Armed with clearly defined risk control mechanisms, they are effective in mitigating identified risks and proactively adapting trials as appropriate.
Much of this can now be managed through technology that automates risk analyses, centralizes on- and off-site monitoring, and preserves all documentation in system-maintained audit trails.
Such platforms aggregate study data from a host of existing systems and data sources - including wearables, electronic health records, public data banks, and trial-generated sources. Then, harnessing artificial intelligence, machine learning, business intelligence, and automation, they apply analytics based on pre-determined, trial-specific risk triggers, then visualize the results so that variances and key risk indicators are instantly identifiable. Such platforms also support permission-based sharing, so that the correct data are always available within key communication and reporting pathways, to enable and track data-driven, transparent decision-making.
This oversight enables researchers to ensure that clinical trial data is accurate and verifiable, upholding patient safety and regulatory compliance, while simultaneously improving efficiency, saving time, and controlling costs for trials, regardless of trial design or data source. In short, such technology can enable the future of clinical trials. Yet, ICH guidance is complicating its use.
Despite Technology Solutions and Industry Support, at Present Nothing Has Changed
Although ICH E6(R2) supports some innovations - such as centralized monitoring - it does not fully address the many advances in trial design, data sourcing, testing, and technologies that have emerged even in the past four years.
For instance, it asks that researchers avoid unnecessary data collection to minimize the amount of data that needs to be verified. Yet, mHealth devices, which help minimize the patient burden, capture reams of data, only some of which is valuable to a specific trial. To reduce their burden, instead of limiting the amount of data collected, researchers should be freed to only monitor that subsection of data which is relevant to their trial.
New trial designs pose even greater challenges. Again, ICH E6(R2) asks that researchers avoid “unnecessary complexity (and) procedures.” Yet adaptive trials are predicated on ongoing updates from constantly refreshed data input. Again, validating every piece of data creates potentially fatal delays that undermine the value of the trial design. Similarly, platform trials, governed by a master protocol document, do not include all elements recommended in the current guidance - but that lack is integral to their design, not an omission to be fixed.
Even something as simple as a patient intake form may be affected by the lack of clarity in the ICH E6(R2) guidance. Pages of questions may be standard for intake forms, yet in truth only two questions are critical: Does the patient meet inclusion/exclusion requirements? Did the patient consent? It is also not clear that e-consent is acceptable, even though it is far simpler for patients.
In sum: It is challenging to apply the current ICH E6(R2) standards while taking advantage of technological advances, new study designs - and, ironically, the full potential of risk-based quality management. Instead of being free to embrace advances, trials are burdened by multiple layers of well-intentioned “GCP-motivated” processes, which stifle research. From the broad to the specific, from trial design to intake forms, ideally researchers should be able to fit monitoring and other actions to the trial’s needs, rather than follow broad guidelines that may no longer be applicable.
Now, ICH E6(R3) will be structured to actively guard against these unintended encumbrances.
ICH E6(R3) Should Set the Stage For The Future Of Clinical Trials
To match the pace of innovation, researchers must be able to balance changing data needs and rapid data availability against the demand for completeness and verifiability. With ICH E6(R2) causing roadblocks, organizations across the clinical trial industry called for change. ICH has listened, and a complete rewrite of the guidelines is underway. The new guidance, to be adopted across all regulatory agencies, is anticipated this year.
Like all ICH guidance, ICH E6(R3) is being developed through an inclusive, consensus-driven, multi-stakeholder, five-step process. It will be released in two parts:
- Annex 1, anticipated in the fall of 2021, will focus on interventional clinical trials, considering the guiding principles as they relate to the use of unapproved or approved drugs in a controlled setting with prospective allocation of treatment to participants and collection of trial data.
- Annex 2, due 12-18 months later, will focus on nontraditional interventional clinical trials, considering the guiding principles as they relate to the use of nontraditional clinical trial designs, such as pragmatic and decentralized clinical trials, as well as those trials that incorporate real-world data sources. It also will delve into novel areas not considered in previous versions and will address a broader approach to clinical trials incorporating the potential impact of technology.
While many people will weigh in on the final output, there is clear consensus on which sections require the most focus. In a recent survey, active researchers working in 153 countries worldwide rated the most pressing need as “implementing systems that assure quality,” and 45 percent listed monitoring as a prime focus.
It is hoped that the new guidelines will provide flexibility to accommodate the increased role of technology - from e-signatures and e-documentation to the full range of data sources – including emerging technologies and advances like machine learning and artificial intelligence. These, in turn, will support and enable the innovative trial designs that don’t easily fit into ICH's current dated guidelines.
Revised ICH Guidelines Will Help Realize the Power of RBM
Designing, developing, and running clinical trials is inherently complex. Every day, technological advancements offer more options for data collection, trial design, monitoring, and verification. These may add further complexity, simply because the trial path is no longer clear-cut. Yet, technology can also uncomplicate things. Automation can help streamline processes and speed analysis, powering RBQM and RBM.
By combining RBM and technology, researchers cut through clinical trial complexity. They reduce the burden on patients and investigative sites, while increasing participation and enrollment in clinical trials. They bring together the relevant metrics and data necessary to increase efficiency, patient safety, and data quality. They leverage frameworks which support cross-functional engagement and enable confident decision making. They even manage costs while accelerating regulatory approval of new drug candidates. No wonder there is global industry-wide support for embracing these methods.
Yet current industry standards, codified in ICH E6(R2) have left ambiguities that undermine the very advantages of adopting RBM. ICH E6(R2) requires researchers to develop a systematic, prioritized, risk-based approach to monitoring clinical trials - but it leaves legacy guidance on processes. Hence the universal demand for a rewrite of the guidelines.
These updates must think through and support the implementation not only of RBM, but of a host of innovations - improved and more efficient approaches to clinical trial design, conduct, oversight, documentation, and communication. That, in turn, will pave the way for tomorrow’s faster, more nimble trials, that will speed critical new therapies to patients worldwide. We all excitedly await Annex 1 in the fall of 2021.
References
- Duke Margolis, FDA. 2019. Improving the Implementation of Risk-Based Monitoring Approaches of Clinical Investigations [Video File]. https://www.youtube.com/watch?v=xp8Wp0Upuvo