The International Council for Harmonization (ICH) first came out with its E6 Good Clinical Practice guidelines in 1996, outlining the responsibilities of all participants in clinical studies. They updated the E6 GCP guidelines 20 years later, requiring a risk-based approach to design and conduct; however, in the face of concerns that the guideline didn’t go far enough to address rapidly evolving technologies and other aspects, the ICH is undertaking a full rewrite, named ICH E6 (R3).
Kristin Mauri, director of solution services with clinical trial data solutions provider Remarque Systems, spoke with Outsourcing-Pharma about what sites and sponsors should expect when the revised guidelines finally land, the timing, and how best to prepare.
OSP: Please tell us about the ICH E6 GCP guidelines — why they were put forth back in 1996, who they were designed for, and how they helped.
KM: They were first published in 1996 as electronic medical records (EMRs) proliferated. Designed for clinical trial researchers — and by extension both sponsors and CROs — the new guidelines provided international standards that created cross-border consistency, not only for recording but more broadly for ethical and scientific quality.
These new standards addressed the design, conduct, and reporting of clinical trials, and created tremendous industry-wide efficiencies. It meant that trials didn’t have to be duplicated in every potential market, drug-market applications had a uniform structure, regulatory review was simplified, and the chances of a new therapy receiving first-cycle approval increased. That was a huge step forward for the industry.
OSP: Then, 20 years later, the ICH amended them — could you please share your perspective on those changes?
KM: Of course, the clinical trial landscape continued to evolve, and the 2016 ICH E6(R2) recognized that. Among other things, ICH E6(R2) included updated standards for EMRs, since they, themselves, had changed. It also encouraged the use of a risk-based approach in the design and conduct of clinical trials, which mirrored the way trials were (and are) increasingly being run.
Specifically, it asked that research teams identify, during protocol development, the data and processes critical to ensuring patient safety and the reliability of trial results, and the risks to such critical data and processes; that they evaluate the likelihood of such risks; and that they document and report any such risks during the trial.
But ICH E6(R2) didn’t account for the dramatic evolution of technologies, nor the increasingly innovative trial designs these technologies enable. For instance, decentralized clinical trials (DCTs) gather input from a range of technologies, including patient-reported outcomes, wearables, and mobile data collection devices. In adaptive trials, investigators modify trial parameters in real time.
Neither works well within the ICH E6(R2) guidelines, which still imply the need to verify every piece of data, regardless of its import to the trial endpoints. So even though ICH E6(R2) explicitly states that researchers should avoid unnecessary complexity, in practice trials can sag under the burden of processes designed to comply with ICH E6(R2) standards. The forthcoming new rewrite will address those issues.
OSP: What are your thoughts on the ICH opting for a full rewrite, versus an update — was such an overhaul warranted?
KM: The 1996 update was an addendum, providing additional guidance without changing the existing text — and now we are living with the unintended consequences. An update needs to fully consider the entire clinical trial landscape —both the current landscape and its future direction.
Now a broad array of stakeholders — sponsors, researchers, government representatives, industry professionals — are working cooperatively to draft the new guidelines. They are taking a five-step approach that includes widespread public review.
They are also focusing first on strategy — not only considering existing gaps but emerging needs and opportunities. Hopefully, this will build in much-needed flexibility that will enable the guidelines to be adaptable enough to adjust to progress.
Inevitably, the future will bring technologies and trial designs and processes and other considerations that have not yet been conceived; this time, we should be ready. So yes, a complete overhaul was warranted.
OSP: What do you think sites and sponsors should expect in the rewrite?
KM: ICH E6(R2) championed a proportionate, risk-based approach to the design and conduct of clinical trials. Unfortunately, the guidelines weren’t clear on how to achieve that approach.
ICH E6(R3) will continue the focus on risk-based monitoring (RBM) while clarifying how to implement it. Specifically, we should expect guidance on remote assessment and monitoring, and a framework for utilizing all available (and future) technological tools and innovations to ensure trial integrity while alleviating the burden of verifying non-crucial data.
These changes will bring a host of advantages. They should reduce the burden on patients, therefore increasing enrollment. They should also simplify operations for trial sites, lowering costs while leveraging access to real-time information. And, because they support a structured approach to risk-based quality management (RBQM) they should help accelerate regulatory approval.
OSP: Could you please talk about the timing?
KM: The release of ICH E6(R3) is planned in two stages. Annex 1 is expected in the fall of this year. It will primarily focus on interventional clinical trials, setting out the guiding principles for the use of both approved and unapproved drugs in a controlled setting, in which treatment is allocated to patients and trial data is collected.
Annex 2 is expected 12 to 18 months later — fall of 2022 or spring of 2023. It will address non-traditional clinical trial designs — DCTs, adaptive trials, pragmatic trials, and trials that harness real-world data. It will also tackle the impact of technology and other areas previous versions have not addressed.
OSP: How should trial teams prepare for the changes?
KM: Certainly, training all trial staff on the new guidelines is an essential first step in preparing for the changes. Companies should also closely examine their internal policies and procedures.
It is likely that many current processes are in place simply to meet ICH E6(R2) guidelines; these can be adjusted or eliminated once the changes are instituted, and companies would be wise to begin rethinking them now, so they are ready to act efficiently. Concurrently, they may want to begin crafting new processes to take advantage of technological advances and to truly embrace RBQM.
OSP: What questions should a clinical trial professional ask when assessing their operation’s likely readiness for the update?
KM: A key advantage of the new ICH E6 (R3) guidelines should be the elimination of many processes which may have hampered the adoption of innovations such as risk-based trial design and DCTs—and the analogous uptick in adoption of technologies that can streamline trial operations.
The question industry professionals should be asking is whether their organization is ready:
- Have they already adopted RBQM? If so, what burdensome layers of checks and cross-checks can be eliminated?
- How will that affect trial execution, monitoring, and personnel and technology requirements? How are they positioned to execute DCTs?
- Do they have the necessary partnerships in place?
- Are they prepared to ensure the quality and diversity of the reams of data DCTs generate?
- Are teams well-versed in integrating technology into trial design?
- Are they sufficiently data literate to take advantage of those technologies, to be able to analyze data in real time and use it to speed decisions and shift inquires?
OSP: Can you share how companies like Remarque might assist clients in preparing for the change and working toward a smooth transition?
KM: Technology is going to play an increasingly large role in clinical trials going forward — as is the mandate for risk-based monitoring as an essential part of RBQM. Researchers will need to continuously monitor leading quality indicators and potential risks, based on real-time information.
Technology that automates risk analyses centralizes both on- and off-site monitoring, and preserves all documentation in system-maintained audit trails can simplify these processes. Adopting them now can help companies develop and normalize RBQM standards so that they are inherent to their way of doing business by the time ICH E6(R3) is passed.