Clinical trials have changed significantly over the past decade. Remote visits, wearable devices, electronic health records and home healthcare services have moved from emerging concepts to established parts of modern research. These approaches can improve access, reduce participation burdens and support more flexible trial designs. They also introduce new challenges around oversight, data quality, technology management and participant safety.
Annex 2 of ICH E6(R3) has been developed with these changes in mind. Rather than creating a new set of Good Clinical Practice (GCP) principles, it builds on Annex 1 by explaining how existing GCP expectations should be applied.
Annex 2 will come into effect on 15 January 2027, following ICH adoption in June 2026. While the principles and Annex 1 of ICH E6(R3) have already been implemented, Annex 2 provides additional guidance for trials incorporating decentralized elements, pragmatic designs and real-world data sources.
Annex 1 sets out the overarching GCP principles for clinical trials, while Annex 2 provides additional considerations for studies that move beyond the traditional site-based model.
For sponsors, investigators and research teams, Annex 2 is less about changing the rules and more about recognizing that the way clinical research is conducted has evolved.
Why Annex 2 was introduced
When ICH E6 was first published in 1996, most clinical trials followed a familiar structure. Participants attended scheduled visits at research sites, study procedures were performed by site staff and trial data were collected specifically for the study.
Today’s trials often look very different.
Participants may complete questionnaires through smartphones, use wearable devices that continuously collect health information, receive investigational medicinal products at home or have research nurses visit them outside the traditional site setting. Researchers are also making greater use of electronic health records, disease registries and other real world data sources.
Many organizations have already adopted these approaches before Annex 2 of ICH GCP (R3) will be introduced. In many cases, teams applied existing GCP principles to new situations as best they could. Annex 2 provides greater clarity by explaining how established principles should apply in these more complex research environments.
The full ICH E6(R3) guideline, including Annex 2, is available on the European Medicines Agency website.
Decentralised trial elements become part of accepted practice
One of the most significant developments in Annex 2 is its recognition of decentralized clinical trial elements.
Remote consultations, electronic informed consent, wearable technologies, home healthcare visits and direct to participant delivery of investigational medicinal products are recognized as legitimate approaches when they are appropriate for the study and the participant population.
This does not mean that every trial should become decentralized. Annex 2 of ICH GCP (R3) does not promote a particular trial model. Instead, it acknowledges that different approaches may be suitable depending on the research question, risks involved and needs of participants.
The key principle remains the same: moving activities away from the research site does not reduce the responsibilities of sponsors or investigators.
Participant safety, medical oversight, informed consent and protocol compliance remain essential regardless of where trial activities take place.
For research professionals, this means thinking beyond the technology itself. Teams need to consider practical questions such as how participants will be trained to use wearable devices, what support is available if a digital tool fails, how missed remote visits will be managed and how adverse events will be reported during home-based activities.
Protecting participants in more flexible trial models
As more trial activities take place remotely, participant protection requires careful planning.
Electronic consent can make participation more accessible, but organizations must ensure that participants receive understandable information, have sufficient opportunity to ask questions and can make informed decisions about taking part. Processes should also address identity verification, documentation requirements and accessibility needs.
The same principles apply whether consent takes place in person or electronically. Technology may change the method, but it does not change the responsibility to ensure participants are properly informed and protected.
Real-world data moves further into clinical research
Another important theme within Annex 2 is the increasing role of real-world data.
Electronic health records, disease registries and routine healthcare data can support pragmatic studies, long term follow up and research that reflects everyday clinical practice. These sources may reduce unnecessary duplication of data collection and provide valuable information about broader patient populations.
However, Annex 2 does not suggest that all real-world data are automatically suitable for regulatory research.
The focus is whether data are fit for purpose.
Organizations need to understand whether the data are complete, reliable, traceable and appropriate for answering the research question. They also need to demonstrate that suitable controls are in place to maintain data quality and integrity.
The important question is not only where data come from, but whether they can support trustworthy conclusions.
Quality by Design remains central
A key message throughout ICH E6(R3) is that quality should be built into a study from the beginning rather than checked only at the end.
Annex 2 reinforces this approach by encouraging organizations to identify the activities and data that are critical to participant safety and reliable study results. Resources can then be focused on areas where risks are greatest.
This proportionate approach is particularly important for decentralized and pragmatic trials. Traditional site-based processes should not simply be transferred into new trial models without considering whether they remain appropriate.
More data does not automatically mean better research. Collecting information that does not support participant safety or the reliability of results may increase complexity and burden without improving study quality.
Technology creates opportunities and new responsibilities
Digital technologies have opened the door to more flexible clinical trials, from wearable devices and mobile applications to cloud based systems and electronic source data. Increasingly, research organizations are also exploring artificial intelligence (AI) and machine learning tools to support activities such as data review, monitoring, analysis and decision making.
While AI offers significant opportunities, the same principles that apply to other digital technologies also apply to AI enabled tools. Organizations need to understand how systems are developed, validated and used, and they need to consider whether outputs are reliable, explainable and appropriate for their intended purpose.
AI should not replace appropriate clinical judgement or oversight. Research organizations remain responsible for ensuring that decisions affecting participant safety, data quality and trial conduct are subject to suitable review and governance.
As with other technology platforms, teams need to consider data integrity, privacy, cybersecurity, access controls and audit trails. They also need to understand how data are generated, processed and transferred when AI systems are involved.
Technology can make participation and trial management easier, but it must always support confidence in the accuracy, security and reliability of clinical research results.
Oversight cannot be outsourced
Modern clinical trials often involve multiple organizations working together. Home healthcare providers, central laboratories, imaging companies and technology suppliers may all contribute to trial delivery.
Annex 2 reinforces a long established GCP principle: tasks can be delegated, but responsibility cannot.
Sponsors remain accountable for ensuring that vendors are appropriately selected, qualified and monitored. Investigators should also understand how external providers contribute to participant care and data collection.
Oversight responsibilities now extend beyond traditional site teams. Training may be required for vendors, healthcare professionals and technology providers involved in trial activities.
As trials become more distributed, clearly defined responsibilities, effective communication and appropriate oversight become increasingly important.
What research professionals should consider now
Many organizations are already using decentralized approaches, digital technologies and alternative data sources. Annex 2 of ICH GCP (R3) provides an opportunity to review whether existing processes have kept pace with these developments.
Research professionals should consider:
- Do standard operating procedures adequately cover remote trial activities?
- Are staff trained to manage decentralized procedures and digital technologies?
- Do quality systems support the use of real-world data and multiple data sources?
- Are vendor oversight processes proportionate to the level of risk?
- Can the organization demonstrate where critical data originated and how it has been managed throughout the study?
- Are participant support processes suitable for remote and hybrid trial models?
Answering these questions will help organizations prepare not only for Annex 2, but also for the continued evolution of clinical research.
Looking ahead
Annex 2 of ICH GCP (R3) does not lower the standards expected of clinical trials, nor does it replace the principles established within Good Clinical Practice. Instead, it recognizes that research has moved beyond the traditional site-based model and provides practical guidance for applying GCP in today’s increasingly connected research environment.
For research professionals, the message is clear. Innovation and flexibility should improve the participant experience and support high quality research, not replace the fundamentals of GCP.
Organizations that embrace new approaches while maintaining strong governance, thoughtful study design and effective oversight will be best placed to meet the expectations of ICH E6(R3) and support the next generation of clinical research.
For more background on ICH E6(R3), you may also find our previous articles helpful:
- Implementation of ICH E6(R3)
- ICH GCP R3: What Should We Expect? Part 1.
- ICH GCP R3: What Should We Expect? Part 2.
Stay ahead of the evolving clinical research environment and Annex 1 and Annex 2 of ICH GCP (R3) with GCP Central’s ICH GCP training.
Our courses cover the latest R3 updates, including the impact of decentralized trials, risk-based quality management and new approaches to trial oversight. Designed for research professionals, our training provides the practical knowledge needed to apply current GCP expectations with confidence.
Speak with our team to find the right training solution for your organization.
