Impact of ICH E6 R3 on Clinical Trials

ICH E6(R3) was written to incorporate more flexibility into Good Clinical Practice (GCP) guidelines, with the authors acknowledging that as trials become more diverse, the principles that support their conduct need to as well. In planning for R3, ICH noted that it intended to address the complexities of clinical trials in the current global regulatory climate.

The key principles of R3 are further supported by Annex 1, which outlines how the principles can be applied. While Annex 2 is still in development, it is expected to address additional considerations for nontraditional clinical trials, including decentralized elements in clinical trials and real-world data sources. R3 not only expands on the concepts seen within ICH E6(R2) but also aligns with concepts seen in other existing ICH guidances, such as E8(R1).

But what impact do these principles have on the conduct and oversight of clinical trials?

The ethical principles first outlined in the Declaration of Helsinki still ring true—first and foremost clinical trials should be designed to ensure the rights, safety, and well-being of the participants. Although key ethical principles remain unchanged over the years, R3 emphasizes the importance of gaining inputs from a wide variety of stakeholders (including patients) as clinical trials become more complex, as seen in ICH E8(R1).

Informed consent may be obtained and documented via paper or electronically, however, either method must uphold the previously defined ethical principles and follow regulatory requirements. When utilizing electronic informed consent, security controls should be maintained for the computerized system, and validation should be based on a risk assessment considering the intended use of the system, which, in the case of informed consent, would be higher due to the nature of the data. In addition to the inclusion of electronic consent in R3, ICH also notes the ability to obtain consent remotely, when conducted in line with recommendations from Regulatory Authorities.

Both the investigator and sponsor have responsibilities related to IRB communication and clinical trials should always be conducted in compliance with an IRB approval. The importance of strong IRB oversight and communication proves key in safeguarding the rights, safety, and well-being of trial participants. R3 expands IRB review responsibilities and outlines the requirement for IRB periodic review of the trial to be completed in accordance with applicable regulatory requirements.

Scientific knowledge should support proposed clinical trials, with sufficient information on the investigational product when designing the trial, and through a periodic review once the trial begins. R3 notes a deeper focus on sponsor review of safety information, which may drive updates to protocol, investigator’s brochure, consent form, or other related materials, with references to ICH E2A, E2F, and E19 for more detailed guidance on safety reporting. Period review of scientific knowledge and approaches is expected to determine if modifications to the trial are needed.

Individuals working on trials should have the appropriate education, training, and experience to perform their respective tasks. R3 adds clarity to types of individuals that may be needed across all phases of clinical trials. Similar to R2, R3 outlines responsibilities for IRB, sponsors, and investigators, but with the increasing adoption of computerized systems in clinical trials, individuals also need to be trained on using those systems.

To achieve quality by design, all components in the design of the trial must be carefully planned to maximize the success; and strategies should be in place to avoid, detect, and address any potential non-compliance. An appropriate Quality Management System (QMS) should be in place to support quality throughout the trial lifecycle. As outlined in E8(R1), R3 outlines requirements for the Sponsor to incorporate quality in proportion to risk.

As part of quality assurance procedures, R3 expands clinical trial monitoring procedures, noting that monitoring can be completed remotely if appropriate based on the clinical trial’s monitoring strategy and design. This shows an increase in adoption of technology throughout clinical trials from the R2 release where centralized monitoring was noted as a possibility in exceptional circumstances only. R3 also supports the use of Remote Source Data Verification (rSDV), noting that monitoring also may include secure, remote, direct read-only access to source records.

R3 expands on the principle of applying a risk-based approach to monitoring clinical trials, to support the more complex trials we see today. The processes and risk mitigation strategies of a trial should be proportionate to the importance of the data being collected and the risks to trial participant safety and data reliability. The draft guideline outlines that risks in this context include not only risks to the rights, safety, and well-being of trial participants but also risks to the reliability of the trial results. Risks should be evaluated based on the likelihood of harm, the extent harm would be detectable, and the impact of such harm; and controlled accordingly.

Clinical trial protocols should be written in a way that is clear, concise, and operationally feasible to protect trial participants and generate reliable results. Within R3, Appendix B outlines key requirements of clinical trial protocols and protocol amendments, outlining the need to design protocols to minimize unnecessary complexity and build in adaptability to decrease the number of deviations. In recent years, we’ve seen an increase in decentralized trials, and R3 supports this with notes of decentralized elements in study design, whereas R2 was previously silent on this topic.

Since the development of R2, clinical trials have continued to evolve with new designs and technological innovations. The systems and processes that are utilized for the capture, management, and analysis of data should be implemented in a way that is proportionate to the importance of the data being collected, to provide confidence in the trial results. R3 includes a new section on Data Governance, guiding appropriate management of data integrity, traceability, and security. Both sponsors and investigators are responsible for keeping their records secure and retained for the retention period required by overarching regulations, however, the specific retention periods for IRBs, Sponsors, and Investigators have been removed from R3. The draft guidance also includes service providers as a party to be notified when records are no longer needed.

Although duties may be delegated, the sponsor and investigator are responsible for maintaining supervision and are ultimately responsible for their respective activities. In R3, there is an increased focus on the investigator’s responsibility to protect the privacy and confidentiality of participant’s personal information.

Delegation of responsibilities to service providers is seen throughout R3. While the sponsor may help the investigator identify service providers, the investigator has the final decision on whether the service provider can adequately support the investigator, and the investigator retains the responsibility to supervise any service providers conducting delegated trial activities. Service providers also have the responsibility to report any incidents that may impact the safety of participants or trial results.

When using computerized systems in clinical trials, the responsibilities of the sponsor, investigators, and the activities of other parties concerning the system should be clear and documented. If systems are deployed by the investigator/institution the investigator is responsible for ensuring appropriate access and controls are in place; however, even if the system is deployed by the Sponsor, the investigator is still responsible for ensuring the systems are used as specified in the protocols and other instructions.

Investigational Products (IP) used in clinical trials follow Good Manufacturing Practice standards to ensure that trial participants are receiving high-quality products. R3 adds additional guidance for ensuring quality and management of IP to align with randomization and blinding processes; product handling, shipping, and labeling should follow applicable regulatory requirements.

As you can see above, the long-anticipated R3 amendment will continue to drive clinical trials ahead, supporting technological innovations and complex clinical trials. Will you be ready?

This information is an overview from Florence’s Compliance Team and is not meant to serve as official guidance or review of appropriate regulations. If you have any questions on how Florence’s Site Enablement Platform can be used in compliance with ICH GCP, reach out to your Florence contact or schedule a demo.