Rewriting the Rules: How to Prepare for ICH E6 (R3)

By: Kristin Mauri - Director of Solution Services - Remarque Systems

The International Council for Harmonisation (ICH) establishes industry-wide standards for clinical trials - and those standards are undergoing a complete rewrite, affecting the ways trial data is monitored, analyzed, and de-risked. These changes are being developed both at the behest of and with extensive input from a wide range of industry insiders; and they are explicitly aimed at helping eliminate complexity, enabling sponsors and researchers to take advantage of exciting new technologies and the innovative trial designs they make possible. Yet, changing standards will inevitably require changing processes and procedures to meet those standards; it will pay to be prepared.

The Historical Perspective: ICH Was Designed to Make New Drug Development and Registration More Efficient

In 1996, the ICH created the first version of ICH E6 Good Clinical Practice (GCP) Guidelines, which described the responsibilities of all participants in conducting clinical trials. Yet, as the decades passed, the industry evolved. Remarkable innovations spurred wide-ranging new ways to design and conduct trials and to collect, store, and analyze data. As a result, the old guidance seemed inadequate. In 2016, the ICH amended their guidelines emphasizing the value of a systematic, prioritized, risk-based approach to monitoring clinical trials. ICH E6(R2) recommends that sponsors:

• Identify data and processes critical to ensuring patient safety and the reliability of trial results, and the risks to such critical data and processes during protocol development
• 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 determine the effectiveness of risk-control efforts and consider emerging knowledge and experience

To support these recommendations, ICH E6 (R2) states that researchers may choose on-site monitoring, centralized monitoring, or a combination of the two. That is a huge step forward from ICH E6 (R1) and emphasizes the vital importance of data management and analysis throughout the trial. It still does not, however, address the various changes in trial design, data sourcing, testing, and other technological advances that have become increasingly essential to the clinical trial landscape.

Indeed, many of the best-intended rulings have increased complexity. For instance, ICH E6 (R2) asks that researchers avoid unnecessary data collection to minimize the amount of data that needs to be verified. Yet mHealth devices, which enable remote data collection, also produce a deluge of data, much of which is not relevant to a specific study. As it currently stands, to remain in compliance, every piece of that data must be verified - an unnecessary and Herculean task. It would seem preferable to allow researchers to collect as much data as they like, but only monitor the subsection that affects their trial outcomes.

The complexity escalates with new trial designs, such as adaptive trials (which are predicated on ongoing updates from constantly refreshed data input) and platform trials (whose design deliberately omits many elements recommended by ICH E6 (R2)). Not surprisingly, in 2020, industry groups sounded the call for change. 

Now the ICH is undertaking a full rewrite of the ICH E6 guidance. The rewrite, ICH E6 (R3), is expected to provide comprehensive new guidance on fresh solutions that have emerged in the increasingly intricate clinical trial landscape.

The Process of Revision: Developed by A Broad Coalition of Industry Leaders, The New Guidelines Are Due in 2021

In a bid to avoid the unintended complexity resulting from ICH E6 (R2), the new rewrite will be multi-stakeholder- and consensus-driven. In fact, it was even initiated by consensus when the Clinical Trials Transformation Initiative surveyed 327 researchers working across 153 countries to solicit their opinions concerning the areas of ICH E6 (R2) that do and do not need updating. 

Responding to that survey, stakeholders clearly indicated that the new guidance should help:

• Implement systems that assure quality
• Establish monitoring as a prime focus

Again, industry-wide, data management and analysis are seen as a primary focus, recognizing that new technologies can significantly facilitate and de-risk these processes. In June 2020, a virtual gathering of the Clinical Trials Transformation Initiative probed the issues more deeply. An international group of industry, research, and regulatory body representatives shared their concerns about ICH E6 (R2) and their hopes for ICH E6 (R3). These speakers universally praised the ICH for setting critical global standards. At the same time, they sought clarity around the flexible options for trial design and data sources and the use of remote technologies. The key areas for review and revision include:

• Safety of trial participants
• Remote assessment
• Remote monitoring
• Ability to leverage existing infrastructure
• Identification and prioritization of critical processes
• Employment of all available technological tools and innovations to ensure trial integrity
• Effective communication

Their shared focus on remote assessment and monitoring reflects current trends in clinical trials: the increase of remote data collection devices, such as wearables and other mHealth technologies, and the corresponding rise in decentralized clinical trials (DCTs) of all kinds. In parallel, these industry leaders are seeking the ability to harness all the advantages of new monitoring technologies, platforms that can flag potential risks in real-time, pin-pointing critical areas for examination, thus increasing safety while streamlining processes. It’s a modernized approach to risk-based quality management.

Armed with these key areas for review, the real work has begun, following a rigorous five-step process involving both regulators and industry members:

1. The working group drafts and approves a document
2. The document moves to the ICH assembly and international regulators for review and approval and/or revision
3. The document then goes to the public for review and approval and/or revision
4. The ICH adopts the guidance
5. Each region implements ICH E6 (R3)

ICH E6 (R3) will be developed and implemented 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 non-traditional interventional clinical trials, considering the guiding principles as they relate to the use of non-traditional clinical trial designs such as pragmatic clinical trials and decentralized clinical trials, as well as those trials that incorporate real-world data sources. It will also delve into novel areas not considered in previous versions and address a broader approach to clinical trials incorporating the potential impact of technology. 

With the anticipated release of Annex 1 fast upon us, it is time to start preparing, so you can take immediate advantage of the changes and updates.

Get Ready for Implementation: Preparing for The Adoption of ICH E6 (R3)

The new ICH guidance should alleviate complexity around many of the processes and tools researchers are already harnessing in clinical trials - especially as it relates to risk-based monitoring (RBM). Specifically, as previously noted, we should expect guidance on remote assessment and monitoring and a framework for utilizing technology that will be elastic enough to encompass both current platforms and future innovations, ensuring trial integrity while alleviating the burden of verifying non-crucial data. 

If a core focus of the new guidelines is RBM, in preparing for their implementation, sponsors and researchers can consider whether their trial designs currently use best practices for RBM. In addition, they can identify critical gaps in skills and systems by asking themselves some key questions:

• Do our policies and procedures adequately address risk?
• Do our practices focus on quality control?
• Have we taken measures to ensure the quality and diversity of the increasing reams of data generated by mHealth devices?
• Can our teams monitor leading quality indicators and potential risks?
• Have we adopted new technologies that can help instantly pinpoint risks when they show up amid reams of data?
• Do our teams understand how to use that technology, and how to incorporate it into trial designs?
• Are our teams data savvy - or even data literate?
• Do we have the expertise and technology to support remote monitoring?
• Are we designing every new trial around RBM?

Based on the answers to these questions, clinical trial teams can adjust their internal policies and procedures, streamlinetheir operational processes, begin training their employees, and implement new technologies that can smooth the path and enable teams to take immediate advantage of the guidelines once they are officially adopted.

One additional idea: Trial teams can examine the proposed guidelines during the public review phase to identify any areas that will create dramatic new opportunities. This is a chance to look in-depth at each recommendation and how it will impact current processes, whether it will require new skills, and what new data management technologies may facilitate following its stipulations - specific insight may further accelerate confident preparations. 

Finally, once the guidelines are approved, in-depth training on their stipulations, how they differ from ICH E6 (R2), and what that means to trial operations is in order.

Fueling the Future: New Best Practices Take Advantage of Technological Innovations

Of course, the industry continues to shift. While ICH E6 (R2) recognized the importance of RBM, it did not anticipate such recent developments as DCTs and the associated assortment of apps, wearable devices, and other remote technologies for data collection and management. These fast-evolving innovations now dominate the clinical trial landscape; this is only likely to grow exponentially as new developments support as yet inconceivable trial designs. Nevertheless, these are the paths to the future, and ICH E6 (R3 - and its successors - will help sponsors and researchers take full advantage of them.

Kristin Mauri has more than 25 years of clinical research experience and eClinical technology implementation at pharma, biotech and CRO organizations. Prior to joining Remarque Systems, Mauri was the Global Head of Risk Based Monitoring at BioClinica, where she was responsible for overseeing the RBM technology and services practice. Prior to that she held positions at Oracle, Abbott Labs, and Covance. A recognized thought leader and industry speaker, Mauri has presented extensively on clinical operations topics in the areas of Risk Based Monitoring, Quality Management and Clinical Trial Forecasting and Budgeting. Mauri's educational credentials include an MBA from Lake Forest Graduate School of Management, MGH Boston master's program coursework in clinical investigations and a bachelor's degree from Pennsylvania State University.

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