Clinical Trial Evolution: The Drive to Update ICH E6

Exciting new clinical trial technologies promise greater protection for data integrity, patients, and even the broader public health, while streamlining trials and reducing costs. Industry guidelines not only encourage but demand their use. Yet researchers still may not be taking full advantage of these advances. At issue: lack of clarity in ICH E6 (R2), the current version of the International Council for Harmonization (ICH)'s "Guidelines for Good Clinical Practice." Fortunately, spurred by member organizations, ICH is undertaking a full rewrite of the guidelines to be adopted across all regulatory agencies. The new guidance is anticipated in 2021.

ICH E6(R2) included a focus on a proportionate, risk-based approach to the design and conduct of clinical trials. ICH E6(R3) will further spotlight risk-based monitoring (RBM) and remove barriers sponsors may have encountered in adapting this approach. This should have many downstream advantages:

• Reducing the burden on patients and investigative sites, while increasing participation and enrollment in clinical trials
• Helping sponsors and contract research organizations (CROs) manage costs, while accelerating regulatory approval of new drug candidates
• Enabling sponsors to adopt a quality management strategy that embraces technology and leverages access to real-time information to drive a more structured approach to risk

Since ICH E6(R2), clinical trials have continued to evolve. This new guidance will help ensure that sponsors can harness the new designs and advances made possible by technological innovations.

Some history: ICH was designed to make new drug development and registration more efficient

Three decades ago, as electronic records became increasingly common in the clinical trial landscape, an issue arose. Without common standards, the format of an electronic document could vary dramatically across regions. The need to harmonize became glaringly obvious, and an international committee went to work.

The ICH GCP, first published in 1996, set international standards for both ethical and scientific quality; they addressed the design, conduct, recording, and reporting of clinical trials. As a result, industry-wide consistency led to well-structured drug-marketing applications, a rapid and efficient regulatory review process, and a higher likelihood of first-cycle approval.
However, the clinical trial landscape has fundamentally changed since 1996. Technology has given us wide-ranging new ways to collect, store, and analyze data. New trial designs—adaptive trials among them—have new ways of using data. Clinical trials themselves have become increasingly complex—and investment-intensive. And global operations require progressively greater division of tasks across multiple functional teams, organizations, and locations. This all conspires to put tremendous pressure on sponsors, particularly resource-constrained small biotech and specialty pharma companies.

A 2016 addendum to ICH E6 provided some extra guidance, including updated standards for electronic medical records, but did not change the existing text. As the clinical trial landscape has continued to advance, this has proven problematic. Consider the rise of adaptive trials, for instance.

Adaptive clinical trials: one innovation driving change in ICH E6

Designing a clinical trial entails mastering uncertainty: What is the best measure of benefit? What factors determine optimal dose or duration? Which inclusion and exclusion criteria target the right patient population? These questions are particularly pressing when researchers are forced to define all key parameters at the trial start and hold them constant throughout execution, as is the case in traditional trial design.

Of course, once the trial actually begins, information accumulates and the answers to the questions become clear. Adaptive clinical trials are designed to take advantage of this input, by allowing researchers to modify trial parameters in real time according to prespecified rules.

Not surprisingly, the data needs of an adaptive trial are quite different from the needs of a traditional approach. Traditional trials—and traditional source data verification—focus on ensuring every data measurement has been taken, and each piece of data is validated.

Conversely, adaptive trials require the ongoing, frequent availability of interim data—snapshots that can be accessed and analyzed rapidly. In the short term, errors and missing data are less critical; they can be updated later.

In addressing quality management, ICH E6 (R2) states that the sponsor should ensure all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures, and data collection. Yet, the guidelines fail to consider the type of trial and the type of analysis within each trial. They have been over-interpreted, with the result that adaptive clinical trials suffer from multiple layers of well-intentioned additional “GCP-motivated” processes. This extra overhead stifles research in resource-limited settings and makes innovative trials substantially more difficult to implement.

Researchers ask that ICH E6(R3) be structured to actively guard against this unintended consequence, to avoid harm to patients and to free clinical research to take advantage of opportunities to move quickly and precisely.

The evolving landscape creates an industry-wide call for change

Many forces have conspired to create tectonic shifts in the ways data are collected and trials are designed and managed. Technology lies at the root of many of these changes. mHealth allows for remote patient assessments, increasing both safety and convenience. Evidence can now be aggregated from multiple digital sources, including real-world data, patient-generated data, and electronic health records. Specialized platforms, driven by machine learning and artificial intelligence, can parse the collected data to instantly discover patterns and pinpoint anomalies that would be virtually impossible to detect unaided. This ability underpins the risk-based monitoring that identifies fraud and patient safety concerns. It also streamlines and accelerates every part of clinical development—from analyzing the DNA of a disease to site selection to patient inclusion and exclusion criteria—all of which frees the very form clinical trials take. Now researchers can effectively run decentralized trials, adaptive trials, multi-modality platform trials, and biomarker and IND-exempt trials, speeding the development of critical new therapies.

Of course, the technology that underpins all this innovation itself continues to evolve, creating new and enhanced study roles and responsibilities—central monitor, data scientist, and medical monitor—and new terms and concepts, including data driven approaches and topdown data review and quality tolerance limits.

Clearly, along with the push to maximize efficiencies comes the need to update the governing protocols—and to agree on the definitions and functions of each new development. The guidelines themselves must also remain flexible, to support a longer planning horizon as clinical trials continue to shift.

By focusing the ICH on strategy, the guidelines could not only ask “Where are the existing gaps?” but also “What are the emerging needs and opportunities?”

The same worries and desires echo across the industry

Stakeholders gathered virtually in June 2020 at the Clinical Trials Transformation Initiative to share their ICH E6 (R2) concerns and their hopes for the new revision.

Deborah Driscoll, Vice President Quality Assurance, Merck Research Labs, spoke on behalf of sponsors, who want to maintain the intent and spirit of GCP, while building a foundation for modern clinical research that harnesses innovative trial designs, permits studies to be conducted in an agile and flexible way, leverages new data sources—and is enabled with modern technology.

Others concurred. Dr. Carol Légaré of Health Canada began by praising ICH E6 for allowing a single set of clinical data to be recognized across jurisdictions, minimizing unnecessary duplication of trials. Yet, she said there have been issues with overinterpretation. Researchers still feel obliged to focus on less important aspects of a trial—such as the completeness and accuracy of every piece of data—often at the expense of such truly critical aspects as carefully managing risks to the integrity of key outcome data. In sum: Health Canada is looking for more clarity around the flexible options for trial design and data sources and the use of remote technologies.

Carla Brishesi of Brazil’s ANVISA (Agência Nacional de Vigilância Sanitária) noted that COVID has illuminated existing trends; for instance, there has been an uptick in remote source data verification of efficacy endpoints and safety data. This requires remote access to patients’ electronic health records and for other trial documents to be uploaded into the cloud. New ICH guidance must consider these movements.

Taking a global perspective, Celia Whitten, MD, PhD, Deputy Center Director of the CBER/FDA praised ICH E6 as an important global standard as evidenced during the pandemic. With clinical trials increasingly being multinational, she feels international standards for GCP can help facilitate clinical development and ensure the integrity of the results. She, too, pointed at some key areas for review and revision:

• 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

With each panelist building on and amplifying connected themes, the trajectory was set for ICH revisions.

The work begins: drafting ICH E6 (R3)

ICH guidelines are developed through a science-based, consensus-driven, five-step process involving both regulators and members of industry. The working group approves a draft document, which is then approved by the ICH assembly and international regulators. The document then goes to the public for review before the ICH adopts the guidance, and each region implements it.

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 nontraditional clinical trial designs such as pragmatic clinical trials 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.

This expected guidance on incorporating technology is likely to be of significant interest to sponsors, as they continue to incorporate new advances.

Anticipated clarification of the role of RBM

The industry is interested in the numerous advantages technology can deliver, with risk-based quality management and its corollary, risk-based monitoring, at the fore. The Clinical Trials Transformation Initiative, a multi-stakeholder public-private partnership co-founded by Duke University and the FDA, conducted a survey probing the areas of ICH E6 (R2) that do and do not need updating. A group of 327 researchers working across 153 countries rated the most pressing need as: “implementing systems that assure quality.” Moreover, 45 percent of those surveyed listed monitoring as a prime focus. The reason can be traced to the 2016 update of ICH E6, RBM became an industry requirement rather than simply a recommendation.

RBM leverages new technologies to assure quality through a comprehensive approach to operational, safety, and quality risks. It uses:

• Risk identification and assessment 
• Risk control and mitigation
• Risk communication and actioning
• Risk review and updating

RBM succeeds through a combination of monitoring strategies including a greater reliance on centralized monitoring and statistical assessments to guide site monitoring visits, and a focus on advanced technical capabilities. Using RBM, clinical trial operations and technologies are designed to bring together the relevant metrics and data necessary to increase efficiency, patient safety, and data quality based on data-driven decisions.

Although ICH E6 (R2) encourages greater efficiency in monitoring, reporting, and archiving, it does not specify how this is to happen. At best, researchers have responded by engaging in much additional paperwork; at worst, they have simply not adopted new methods. The industry now looks to ICH E6 (R3) for clarification.

ICH E6 (R3): Flexible guidelines that can adapt to progress

Researchers have found that technology can enhance, speed, and simplify monitoring. Further, these fresh approaches to monitoring support new trial designs, such as adaptive trials, described above. As technology allows trials to become more geographically dispersed (and the COVID-19 pandemic further encourages working from a distance), thorough and accurate remote monitoring is both completely feasible, given new technologies, and increasingly attractive.

These will not be the final changes to clinical trials. Science, technology, and ingenuity will continue to refine methods and advance possibilities. ICH E6 (R3) must be flexible enough to adapt to designs and technologies that have not yet been conceived. It will succeed by focusing more broadly on principles and objectives, including further advancing the concept of risk-based approaches.

Kristin Mauri is the Director of Solution Services for Remarque Systems