ICH GCP E6 has arrived: Are we ready?

The 2025 ICH GCP (E6(R3)) update[1] is a significant revision of the previous iteration released in 2016, the (ICH E6(R2)) guidelines.[2] The guideline builds on key concepts outlined in ICH E8(R1) General Considerations for Clinical Studies.[3] The revision brings significant changes to the principles and practices of clinical research by implementing risk based methods, enhancing transparency, and promoting efficient oversight. The intent of the guideline is to provide a unified standard to facilitate the mutual acceptance of clinical trial data for ICH member countries and regions by applicable regulatory authorities. This is served by the guideline fostering a quality culture and proactively designing quality into clinical trials and drug development planning, identifying factors critical to trial quality, engaging interested parties, as appropriate, and using a proportionate risk-based approach.

At the time of writing this editorial, several regulatory agencies across the world have started adopting the guideline into their regulations including the EMA (July 23, 2025), Swissmedic (August 15, 2025) and the latest being US FDA (September 08, 2025). Other individual health authorities are expected to follow adopting these guidelines.

As the update focuses in a very detailed manner on integrating technology, enhancing participant safety, and ensuring data integrity let us delve a bit more on these aspects and how it may relate to doing clinical research/trials in India. Since the implementation of NDCT Rules 2019,[4] several key changes are making India an attractive destination for conducting clinical trials. The reduction of timelines for getting clinical trial approval (90 working days) has in itself brought a level of predictability that was missing earlier.

During the COVID-19 period, there was a significant upgradation of the decentralized capabilities in the clinical trials.[5] While sponsors involved in vaccine as well as Therapeutic studies during the pandemic used technology having validated software with provisioned devices (e.g., ePROs, telemedicine, wearables., etc.), there were also many academic trials which used software/devices built from home grown solutions. While many global programs/studies either paused/stopped or slowed down during this period, there were several domestic studies which exposed sites and principle investigator (P.I) to the growing integration of technology in clinical research. Post the pandemic, many of these sites and investigators are comfortable as well as highly aware of using integrated technologies in both domestic and global programs with ease. ICH E6R3 provides guidance on leveraging these technologies to improve efficiency and data collection while maintaining participant safety and data integrity. An example of how this may Play out at the site is that the guidelines address the use of electronic informed consent, remote data collection, and virtual trial visits. As NDCT Rules do not address many of these technology integrations, the guidelines can perfectly address this gap and help investigators navigate technology integration.

The E6 R3 emphasizes a risk-proportionate approach, ensuring that measures and processes are tailored to the specific risks of a trial. This would mean focusing resources on areas with the highest potential impact on participant safety and data integrity. In India, where there continues to be a mix of experienced and clinical trial naïve sites, the sponsors will have to continue to do 100% source data verification (SDV) at the latter sites to ensure that there are no initial compliance or quality issues that are missed. Once there is confidence in the site’s data quality, then there can be a ramping down of the SDV/source data review (SDR) requirements and a move toward targeted SDV/SDR. This approach should be calibrated so as to ensure quality and compliance. Quality by Design (QbD) and Critical to Quality (CtQ) are buzzwords which are now given much more flesh in this iteration. The guideline exhorts sponsors to take care of quality by bootstrapping it from the protocol design stage. Sites and Investigator burden are also due to protocols which are largely designed to collect lot more endpoints than is needed which leads to challenges in managing the participant retention in the study. Sponsors need to imbibe principles of “minimalism” rather than fall prey to “FOMO” so that the downstream CtQ factors in the study from a risk perspective can be conceived in a fit for purpose approach rather than being overbearing, unwieldy, and difficult to implement.

Some of the requirements that are emphasized in E6R3 will require lot more experience and expertise to be built in the ecosystem. Having enhanced patient centricity[6] as the part of the revision is a case in point. E6R3 emphasizes the importance of participant involvement in trial design and conduct encouraging sponsors to actively seek feedback from participants and incorporate their perspectives into trial protocols. In the case of Indian patients, there are two potential issues that sponsors looking to incorporate this aspect will encounter. First would be the representativeness of the patient advocate/advocacy group – in case of urban representatives, they may not be wholly representative of the Indian participant. Second, urban representative would not adequately represent the burden and preferences of the wider population due to factors such as culture, education, and work experience. Hence, consulting with patient advocacy groups or conducting pilot studies to assess participant burden and preferences would still have some areas of challenge.

E6(R3) makes PI oversight nonnegotiable and for sponsors managing studies having Investigators in a trial should definitely make sure that they are truly engaged and not on auto pilot mode. This is the holy grail of clinical trial engagement with a site. If you can get the Investigator to give timely, appropriate and quality oversight of the studies that they are involved in then the clinical research monitor/CRA’s role is much more easy and enables inspection readiness on an ongoing basis.[7]

E6(R3) provides updated guidance on data handling, storage, and transmission, including the use of encryption and secure data storage solutions. The guidance aligns in many ways on the provisions of India’s Digital Personal Data Protection Act, 2023 and Rules, 2025[8] where processing of digital personal data within the territory of India collected online or collected offline and later digitized is stated. There is a strong emphasis on accountability, transparency, and user rights. Sponsors and institutions conducting academic clinical trials would have to address the need for robust data management plans and the implementation of appropriate security measures to protect patient data.

E6R3 is a clarion call for sponsors, investigators, regulators, Ethics committees, and the vendor ecosystem to run an E6R3 gap assessment across Standard Operating Procedures, templates, training plans and then do a refresh of risk based quality management (RBQM)/clinical monitoring plans. Overall, E6R3 is not just a small refresh from the earlier guideline, but it is about building resilient, ethical, and technology integrated trials that work in the real world and it does this by incorporating QbD, RBQM, digital data integrity, and data governance.