What’s New in E6 R3? Investigator Responsibilities, Part 1

Today in our series on ICH GCP E6 R3 we look at the first half of the Investigator Responsibilities section, where “roles and responsibilities” is a running theme and the game of “telephone” makes an appearance.

As we discussed in our last post, the revisions rearranged a lot of the R2 material, but we’ll focus on what’s new and different, except where changed placement suggests some significance.  This blog post deals with sections 2.1. – 2.6.  We’ll discuss section 2.7 on informed consent in a different post, and then sections 2.8 – 2.13 in a third post.

Resources.  This section (formerly “Adequate Resources”) now states that “the investigator may be supported by the sponsor to identify a suitable service provider(s),” a nod to the trend of sponsors hiring resources to support strained site staff, but cautions, “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.”  These statements give investigators increased power to reject sponsor-hired resources but also increased responsibility for oversight of resources.

Another new sentence notes that “trial-related training to persons assisting in the trial should correspond to what is necessary to enable them to fulfill their delegated trial activities that go beyond their usual training and experience.”  This statement marks the first occasion in which a requirement for study-specific training was explicitly addressed in GCP; previously, “training” has been addressed only in the sense of qualifications.

R3 now specifies that agreements for trial-related services must be documented; strangely, the R2 section on “Investigator’s Qualifications and Agreements” did not address agreements.

Medical Care and Safety Reporting.  The statement in R2 that a qualified physician or dentist must be responsible for all trial-related care decisions has been updated in section 2.7 to include “other qualified healthcare professionals in accordance with local regulatory requirements.”  A step has been added to note that healthcare professionals may be involved in the medical care of trial participants “in line with their normal activities and in accordance with local regulatory requirements.”

The R2 section on Safety Reporting has been moved into this section and rearranged so that adverse events are discussed before serious adverse events.  A step has been added to specify that the investigator may delegate safety reporting activities to qualified staff but remains ultimately responsible for participant safety and compliance with reporting requirements.

Communication with the IRB/Ethics Committee. A step was added to the beginning of this section to clarify that either sponsors or investigators may make submissions to the IRB/Ethics Committee, reflecting longstanding practice, and language was updated throughout accordingly.  Steps have been added to specify that IRBs/IECs must be provided with updated investigator’s brochures and participant information; trial summaries, per local requirements or upon request; and changes affecting the trial conduct or increasing participant risk.

Compliance with Protocol. R3 adds a requirement for investigators to “review deviations communicated to them by the sponsor.” Where important protocol deviations occur, investigators are required to “explain the deviation and implement appropriate measures to prevent a recurrence, where applicable.”  Previous negative language about protocol compliance (“the investigator should not implement any deviation from….the protocol”) is restated to emphasize the positive (“The investigator should follow the protocol…”

Premature Termination or Suspension of the Trial. This section has been rewritten to clarify inconsistencies in R2 about responsibilities for reporting termination information to the investigator’s institution, sponsor, IRB/IEC, and regulatory authorities; unfortunately, the rewrite also leaves some gaps. To summarize,

• If a trial is terminated prematurely, the investigator always informs participants.
• If the investigator suspends or terminates their involvement in a trial, the investigator informs the sponsor, IRB/IEC, and regulatory authorities
• If the sponsor suspends or terminates, the sponsor informs the IRB/IEC and regulatory authorities (and, presumably, the investigator, although this is not explicitly stated)
• If the IRB/IEC suspends or terminates, the IRB/IEC presumably informs the investigator (not specified), after which the investigator informs their institution, and the investigator/institution informs the sponsor. It is not clear who informs the regulatory authority.