E6(R3) Good Clinical Practice (GCP) Industry Guideline

In September 2025, the FDA officially adopted the ICH E6(R3) Good Clinical Practice (GCP) guidelines. As the most substantial global GCP framework update since the release of the supplementary documents of E6(R2) in 2016, this new standard, which was officially finalized in ICH Phase 4 in January 2025, is not only an upgrade of regulatory rules but also a profound transformation of concepts.

E6(R3) is based on the "Quality by design" principle proposed by ICH E8(R1), marking the industry's shift from the traditional compliance-by-checklist model to deeply integrating quality, ethics, and transparency into the entire life cycle of clinical trials.

This guideline aims to ensure the protection of the rights, safety, and well-being of trial participants and to guarantee the reliability of clinical trial results. It provides flexible and feasible standards for clinical trials in the context of the new era, to adapt to evolving technologies and methods.

Core Concept

The core change of E6(R3) is to elevate the proactive planning and systematization of quality management to an unprecedented level. E6(R3) requires sponsors to proactively plan quality at the beginning of the trial design and establish a robust quality management system.

The guideline clearly states, "Quality by design should be implemented to identify the factors (i.e., data and processes) that are critical to ensuring trial quality and the risks that threaten the integrity of those factors and ultimately the reliability of trial results."

This requires sponsors to proactively identify and assess potential risks that may affect trial quality, which may exist at any stage of the trial process and system, such as protocol design, subject screening, the informed consent process, randomization, blinding, and the management of study products.

Sponsors must develop corresponding and proportional risk control strategies for these critical-quality factors. For example, in the protocol, quality tolerance limits are set, and if exceeded, the sponsors evaluate whether there are systemic problems and take corrective and preventive measures.

Sponsors are encouraged to focus their resources on the areas that have the greatest impact on trial results and the safety of trial participants, rather than complicating matters unnecessarily, which can improve trial efficiency. In addition, sponsors need to provide detailed descriptions of the methods they have implemented for quality management in clinical trial reports.

Embrace Technology and Decentralization

E6(R3) clearly states that modern clinical trials are no longer confined to traditional clinic settings. The guideline opens up a vast space for the integrated application of digital health technologies (such as wearable devices and sensors) and electronic health records (EHRs), provided that these systems have been verified and are suitable for their intended purposes.

Informed consent

In terms of informed consent, the guidelines also accept remote and digital methods. As long as it can be guaranteed that clear, concise and easy-to-understand information is provided to the participants, and the identity of the participants can be verified in accordance with regulatory requirements, various methods (including text, images, videos, phone calls or video conferences) can be used for the discussion of informed consent and signature of documents.

This flexibility will greatly facilitate the participation of participants in remote areas or with mobility problems in the trials.

Application of new technologies

The guideline also clearly stipulates the application principles of new technologies: New technologies must be adapted to the characteristics of the subjects and the specific design of the trial, rather than the other way around. This reflects the determination of the regulatory authorities to encourage innovation while always prioritizing the protection of subjects.

Non-transferable Supervision and Accountability

E6(R3) emphasizes the non-transferability of supervisory responsibilities, which is the golden rule that sponsors and researchers must always keep in mind. Although the sponsor can entrust the trial-related activities to service providers, and the researcher can delegate some responsibilities to other personnel, the ultimate overall responsibility - including protecting the rights, safety and well-being of the subjects, as well as ensuring the reliability of the trial data - always belongs to the sponsor or the researcher.

The guideline stipulates that all contractual relationships must be clearly defined and documented through an agreement.

• The sponsor must conduct an appropriate assessment and selection of the service provider, and ensure continuous supervision of the key activities they perform.
• For subcontractors, the sponsor also needs to ensure that their activities comply with GCP requirements.
• For multi-investigator trials, the respective responsibilities of each sponsor must clearly be stipulated in the agreement. If not specified, all sponsors shall jointly bear responsibility.

This regulation aims to require applicants and researchers to establish a solid quality management process, and maintain effective control and understanding of the entire trial chain.

Integrity Assurance Throughout the Entire Lifecycle

E6(R3) has set unprecedentedly detailed requirements for data governance and introduced a data lifecycle model. From data capture, metadata management, error correction, data transmission, to data retention and destruction, each step must have clear procedures and records.

System Verification and Security

The guideline requires that the sponsor and the researchers must ensure that all computerized systems used in the clinical trial have been validated to prove that they are suitable for the intended purpose and can guarantee the integrity of the data. The systems must have robust security controls, including user management, access rights, backup and disaster recovery, to prevent unauthorized access and data loss.

Audit Trail

Audit trails are regarded as key metadata for evaluating the testing process. The system must be able to record the initial entry of data and all subsequent changes, including who, when, where, and why the changes were made.

The guideline clearly stipulates that audit trails must not be disabled, and any unplanned blinding, including accidental blinding, must be recorded and evaluated for its impact on the trial results.

Data Sharing and Access

The sponsor must ensure that investigators have timely access to the trial data they are responsible for, so as to make decisions regarding the eligibility of the subjects, treatment, or safety. At the same time, when providing data to the investigators, the sponsor must pay attention to maintaining the blinding method and must not inadvertently disclose treatment allocation information.

These detailed regulations reflect the regulatory authorities' strong emphasis on data integrity, aiming to ensure that the credibility and traceability of data are maintained even in a highly digitalized environment.

Enhancing Transparency and Inclusiveness

E6(R3) further enhances transparency standards for clinical trials, going beyond simple regulatory submissions. The guidelines encourage sponsors to consider directly communicating trial results to participants, and must use "non-technical, easily understandable, and non-promotional" language. This initiative marks a shift in the industry from being solely accountable to regulatory agencies to being more accountable to the broader public and participants.

Subject Recruitment

E6(R3) highlights the importance of inclusiveness in subject recruitment. The guideline states that the subject population of the trial should "represent the group of people who will benefit from the product once it is approved", in order to ensure that the trial results have broad applicability. Although some early trials (such as BE studies) can have a narrow subject population, the guideline warns against unnecessarily excluding specific groups. This is in complete alignment with the efforts of the FDA and global regulatory agencies to promote the diversity and fairness of clinical trials.

Furthermore, the guideline reaffirms the position of informed consent as the ethical cornerstone. It emphasizes that the informed consent process must ensure that the subjects or their legal representatives fully understand all relevant aspects of the trial, including risks, potential benefits, burdens and rights, so that they can make autonomous decisions.

Future Outlook and Action Suggestions

E6(R3) is an action blueprint aimed at guiding the clinical trial industry into a more efficient, safer and more responsible new era. It encourages innovation, but only on the premise that it is based on rigorous science and solid ethics.

Our Suggestion

For sponsors and CROs, E6(R3) represents significant changes in terms of processes, documents and training.

• Update the quality management system

Integrate the risk management approach formally into the design and implementation of the trial protocol, and identify and document the key quality factors and the corresponding risk control measures.

• Reform the informed consent process

Clarify and improve the informed consent materials, and try to use remote or multimedia tools to better participate and understand the informed consent materials.

• Strengthen data governance

Perform risk assessment and validation on all computerized systems used in the test, validate the completeness of the audit trail, and formulate a detailed data lifecycle management process.

• Strengthen supervision and collaboration

Review and sign the agreement with service providers and researchers on responsibilities, clearly define the responsibilities of each party, and set up a good supervision mechanism to form a clear and traceable responsibility chain.

• Maintain openness and inclusiveness

Draw up a trial plan to ensure representativeness in participant recruitment, and set up a timely disclosure mechanism of trial results to the public and participants to improve transparency.

E6(R3) has presented challenges for clinical research, but also brings unprecedented opportunities. Only by keeping up with these changes can one remain competitive in the future wave of pharmaceutical research.

Disclaimer: The above content is compiled based on existing public information and is for reference only.

Our Services

Proregulations has a profound understanding of the FDA's adoption trends and regulatory intentions regarding ICH E6(R3), and is skilled at integrating the FDA's compliance expectations into clients' project frameworks, thereby facilitating a crucial leap from compliance construction to the enhancement of market competitiveness.

• Regulatory interpretation and consultation
• Regulatory training
• Gap analysis
• Quality management system optimization
• Data and document compliance assurance
• Risk control measures development
• Registration submission support

Proregulations, based on the core concepts of the E6(R3) guideline, provides customers with forward-looking strategic interpretation and end-to-end full-cycle solutions, ensuring compliance with the new guidelines and reducing the risk of regulatory inspections. If you are interested in our services, please contact us.

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