ICH E6 (R3) Countdown: Navigating Risk, Readiness, and Site Collaboration

Per the ICH workplan, R3 is expected to be finalized in November 2024. Once R3 is finalized and published by the ICH, timelines for implementation will likely vary depending on the adoption of R3 by the various global regulatory authorities.

R3 “Scope” notes that the guideline applies to interventional clinical trials of investigational products that are intended to be submitted to regulatory authorities. This guideline may also be applicable to other interventional clinical trials of investigational products that are not intended to support marketing authorization applications in accordance with local requirements. For the purpose of this guideline, the term “investigational products” should be considered synonymous with drugs, medicines, medicinal products, vaccines, and biological products.

In terms of “Informed Consent” (Section 2.8), there are a few notable additions. These include:

• Varied approaches (e.g., text, images, videos, and other interactive methods) that may be used in the informed consent process, including providing information to the participant and obtaining consent remotely when appropriate.
• Language related to assent for minors/re-consent if the minor reaches the age of consent during the trial.
• A participants’ trial results and treatment should be made available upon request.

The R3 “Quality Management” section emphasized risk proportionality, noting that the sponsor should adopt a proportionate and risk-based approach to quality management, which involves incorporating quality into the design of the clinical trial (i.e., quality by design) and identifying those factors that are likely to have a meaningful impact on a participant’s rights, safety, and well-being and the reliability of the results (i.e., critical to quality factors as described in ICH E8 (R1)). R3 also notes that the quality management approach implemented in the trial should be described in the clinical trial report (see ICH E3). Section 3.10.1.1, “Risk identification,” highlights that risks that may have a meaningful impact on critical to quality factors should be identified. Risks should be considered across the processes used in the clinical trial (e.g., patient selection, informed consent process, randomization and investigational product administration, data handling, and service provider activities).

R3 expands on the R2 section related to the extent and nature of monitoring, noting that the sponsor should determine the appropriate extent and nature of monitoring based on identified risks. R3 highlights that some monitoring activities may be conducted by different methods including investigator site monitoring (on-site) and centralized monitoring. Organizations can adapt monitoring plans to be tailored to the identified potential safety risks, risk to data quality, and/or other risks to the reliability of the trial results, and focus on aspects of the trial that are critical to quality. The monitoring activities of all the parties involved and the various monitoring methods and tools to be used should be described in the plan (R3 3.11.4).

Section 2.3, “Responsibilities,” highlights key supervision responsibilities of the investigator for all persons/parties to whom the investigator has delegated trial-specific activities. R3 does not provide details on how supervision can be evidenced; other investigator responsibilities could be considered such as review of training records, meetings with trial staff, or timely assessment/review of data collected. Section 3.9, “Sponsor Oversight,” is a new section and highlights a number of sponsor oversight responsibilities.

R3 Appendix C.3.1 includes a list of criteria to determine if a specific clinical trial record generated before, during, and after the trial is essential and should be retained.

Fit-for-purpose can be considered as the application of approaches, study documents, or technology to fit the intended purpose of the clinical trial (R3 introduction). For example, systems and processes that aid in data capture should capture the data required by the protocol and be implemented in a risk-based manner to protect the participants and the acquired data (Principle 9).

R3 doesn’t necessarily change expectations for sponsors’ terms of systems that would be implemented study-wide such as electronic data capture (EDC). Section 4.3 notes that the sponsor should review whether the systems used by the investigator/institution (e.g., electronic health records and other record keeping systems for source data collection) are fit-for-purpose in the context of the trial. There is no guidance in R3 on how to manage scenarios where there is a disagreement.

Section 3.6.10 notes that the sponsor should ensure appropriate oversight of important trial-related activities that are transferred to service providers and further subcontracted.

Section 2.3.1 notes that the investigator may be supported by the sponsor to identify a suitable service provider(s); however, the investigator retains the final decision on whether the service provider intended to support the investigator is appropriate based on information provided by the sponsor. This is specific to providers that will work under the remit of the individual investigator. This is not related to providers that the sponsor selects for study-wide activities (e.g., central lab or eCOA providers).

R3 does not provide details on how supervision can be evidenced. Other investigator responsibilities could be considered such as review of training records, meetings with trial staff, and timely assessment/review of data collected.

The language in section 3.6, “Agreements” (3.6.6), notes that the sponsor should provide information to the investigator on any service provider identified by the sponsor to undertake any activities under the responsibility of the investigator.The investigator has the final decision on vendors that will be under his/her responsibility such as home nursing and not that the investigator has a final decision on vendors that are under sponsor responsibility/used across multiple sites such as a central lab or EDC provider. R3 does not further define what information should be provided; this is an opportunity for collaboration between sponsors and investigators at study start to have these discussions.

Section 2.3.3 notes that the investigator should ensure a record is maintained of the persons and parties to whom the investigator has delegated significant trial-related activities. In situations where the clinical trial activities are performed in accordance with routine clinical care, delegation documentation may not be required. Section 2.3.2 addresses training, noting that trial-related training to persons assisting in the trial should correspond to what is necessary to enable them to fulfil their delegated trial activities that go beyond their usual training and experience.

Under investigator section 2.3. “Responsibilities,” 2.3.2 notes that the investigator should ensure that persons or parties to whom the investigator has delegated trial-specific activities are appropriately qualified and supervised and are adequately informed about the protocol, the investigational product(s), and their assigned trial activities. R3 doesn’t explicitly reference training on the Investigator’s Brochure (IB) for sub-investigators. Appendix A, “Investigator’s Brochure,” notes that the IB purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for and their compliance with many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures.

In terms of oversight, R3 section 3.16.1, “Data Handling,” (w) includes expectations that could be operationalized to support oversight. For example (a) notes that sponsors should have a record (list) of computerized systems used in a clinical trial that includes the use, functionality, interfaces, and validation status of each computerized system, and who is responsible for its management should be described. The record should also include a description of implemented.

While R3 does support adoption of innovative processes and new technologies, there is not an explicit requirement for sites to have site-specific computerized systems (such as electronic health records or eSource systems). R3 does not include language that speaks to a sponsors’ implementation of study-wide computerized systems such as EDC.

The glossary defines essential records as the documents and data (and relevant metadata), in any format associated with a clinical trial that facilitates the ongoing management of the trial and collectively allows the evaluation of the methods used. The factors affecting a trial and the actions taken during the trial conduct to determine the reliability of the trial results produced and the verification that the trial was conducted in accordance with GCP and applicable regulatory requirements. Appendix C.2.1 notes that records should be identifiable, and version controlled, and should include authors, reviewers, and approvers as appropriate, along with date and signature (electronic or wet ink), where necessary.