Proposed ICH-GCP E6(R3) Guidance: Principles in Action

Eric Klaver, Decentralized Clinical Trials Regulatory Director, IQVIA

During the COVID-19 pandemic, the pharmaceutical industry gained experience with the increased decentralization of clinical trial elements, which were traditionally site-based in design and operations. At that critical time, trial sponsors and regulatory authorities turned to the International Council for Harmonization’s (ICH) Good Clinical Practice (GCP) E6 (Revision 2) guidelines to find if digital innovations in trial design, emerging technologies, use of service providers, and more were appropriate, ensuring that participant safety and data were protected. Because the document was issued in 2016, R2 guidelines did not specifically address individual decentralized trial elements and related design requirements.

In May, ICH issued the draft R3 guidance. ICH shifted in direction with this version, going from a process-based approach to one based on principles specific to conducting ethical trial design and quality management. While supporting the use of innovative methods and technologies to improve trial efficiency and success, the R3 guidance focuses on the importance of placing value on patient needs and preferences by designing trials with patients. The ICH GCP guidance will continue to evolve as the industry secures new experiences, solutions, and related insights. In the meantime, it is critical that sponsors, contract research organization (CRO) partners, and site leadership understand what is expected of them as they work to maintain data integrity when using decentralized technologies and processes, keeping patients protected and minimizing burdens for stakeholders.

For investigators specifically, overseeing trial conduct and related data generation, management, and reliability is an expanding responsibility because these key activities can now be done at the site and off-site, such as in the participant’s home or elsewhere and include additional service providers who can access various participant data. Since sponsors have ultimate responsibility for clinical trials, giving investigators and their teams the necessary support to adhere to GCP and regulatory guidance while giving participants flexibility in how they participate is critical. The following are several considerations for sponsors to support investigators and sites as they build a quality trial management system in a rapidly evolving landscape.

Early trial planning: A comprehensive approach

When integrating decentralized elements into clinical studies, investigators take on oversight of protecting the participant’s safety and data while carrying out efficient and quality processes for eConsent, use of wearables, electronic diaries for participant input, data collection via home health providers, and much more. Combine that with diversity in trial population, disease or treatment nuances, phase of development, etc., and sponsors and investigators have quite a bit to think about in today’s landscape. First and foremost is the protection of the participants, which means considering all the regional and national laws and regulations as well as GCP and applicable privacy legislation. Beyond regulatory requirements, incorporating the patient voice into drug development is key to improving engagement and building ongoing trust.

As such, early planning for the requirements noted earlier and more is key to setting up trials on the right track.

Well-defined roles and responsibilities: A starting point

When conducting trial activities off-site, of course, data may be gathered by different methods, including service providers involved, such as mobile nurses or phlebotomists who are accessing relevant participant data, as well as digital technologies that gather data directly from patients. During trial design, clearly communicating who will be responsible for what oversight and at what level is crucial for protecting participant data and the integrity of trial results.

As per the E6 (R3) guidance, trial protocols and agreements should clearly list sponsor and investigator responsibilities during all trial activities, including communication flow and data processing. For example, as home health service providers are assigned specific trial tasks, detailed explanation of their level of involvement and access to specific data should be documented, with the investigator having ultimate responsibility for the trial conduct. The intricate level of nuances included should leave no room for discrepancy on oversight responsibilities. For example, the sponsor can provide a service provider to assist the participant using the technology in terms of set up and ongoing support.

Because this conduct support is contact with the participant outside of tech support, all related activities fall under the investigator’s scope of responsibility. The sponsor can support the investigator by providing and overseeing the service provider’s role on behalf of the investigator. But well-defined explanations of roles and responsibilities are necessary to uphold GCP guidance.

Decentralization and data oversight

Depending on the trial, the amount of continuous data coming through multiple sources (e.g., wearables, eDiaries, trial platforms, etc.), both remotely and on-site, can be hefty, potentially bringing in millions of data points, which fall on investigators to oversee.

Data flow and management

A clear process on how to manage this constant data flow provides a strong foundation for investigators and site teams to effectively take on the task of full data oversight and manage it with reliability in mind. As trials integrate multiple decentralized technologies, platforms and related service providers, a risk-based data management and oversight approach can help them to be audit-ready. This approach can include:

• Creating a data flow diagram so all relevant stakeholders can understand the process in detail. How frequently investigators review incoming data is based on how relevant the data is to patient safety and achieving trial objectives, with a priority on capturing safety events in a timely manner.
• Developing and having a risk mitigation plan in place in case the digital tool does not work as intended. Laying out a thorough plan for addressing immediate need for medical attention will be critical, including what actions should be taken and by whom.
• Regarding digitized tools, sponsors can work with technology partners to ensure these solutions are validated with intended use in mind. This includes:
  • Making sure digital tools are generating required alerts to the investigator regarding defined safety events.
  • Giving the investigator continuous and full access to source data via on-site or off-site methods and ensuring data is directly reported to the sponsor, such as electronic clinical outcome assessment (eCOA) or central lab reports.
  • Minimizing the risk of access to data by unauthorized parties via encryption and other security measures while also defining user rights and methods of access for authorized parties.

Ensuring data reliability

The E6 (R3) guidance puts particular emphasis on the need for data reliability or trustworthiness, and understandably so, given the large amount of data to be collected and reviewed and other complexities that come with decentralizing trial elements.

For one, sponsors should plan and account for participants, investigators, and service providers receiving training on how to use the digital tools included in the trial to ensure that data collection, review, and transmission are conducted properly. In other words, the sponsor should enable site teams and participants to be successful. Additionally, sponsors should ensure educational messaging for participants includes key instructions for communications during the trial.

Participants and service providers alike should receive training on what are considered relevant safety events and related reporting process, including who to reach, in what time frame, and how to manage the event. This is especially important because investigators may not review data in real time. Participants should be able to directly contact the investigator site to report any safety concerns.

Managing a changing landscape

Though the drug development landscape is evolving rapidly, sponsors, investigators, and other key stakeholders may question whether they know how to effectively translate digital transformations into their programs to ensure patients are more engaged and part of the process while securing their safety. However, just as we shifted from paper-based to electronic case report forms, change is a natural part of the equation. Stakeholders are not alone in the process. As ICH recommends, sponsors are encouraged to seek scientific advice from regulatory authorities and other industry advocates regarding the use of decentralized trial elements and related learnings and best practices.

As the industry navigates the future unknowns of patient-centered approaches to trial design, all of us can keep in mind that we are in it together—evolving while ensuring we comply with legislations and industry guidelines to uphold patient safety standards and stay inspection-ready. Patient-centric and decentralized solutions are not the future, they are part of the here and now. But these solutions are evolving and in flux. So, it is a matter of staying up to date.

Eric Klaver, decentralized clinical trials regulatory director, IQVIA