Introduction: Clinical investigators – the physicians or scientists who lead trial conduct at study sites – have always been central to GCP compliance. ICH E6(R3) refines and clarifies several aspects of investigator responsibilities, recognizing the practical challenges investigators face and providing more flexibility in how they manage their duties while maintaining accountability. Key themes include ensuring proper oversight even when tasks are delegated, broadening who can be in charge of medical care, and aligning training with delegated tasks. In this blog, we delve into what’s new or emphasized in E6(R3) for investigators and offer guidance on fulfilling these responsibilities in day-to-day trial operations.

The Investigator’s Core Obligations

First, it’s worth re-stating the fundamentals: Investigators are responsible for protecting the rights, safety, and welfare of trial participants and for ensuring the integrity of the data collected at their site. These core obligations haven’t changed. They manifest in everyday actions like obtaining informed consent correctly, adhering to the protocol, accurately recording data, reporting adverse events, and supervising the study team.

What E6(R3) does is provide more detail on how investigators can meet these obligations in modern trial contexts:

• Qualified Personnel and Delegation (Section 2.3 of Annex 1): Investigators often rely on a team (sub-investigators, study nurses, coordinators) to conduct the trial. E6(R3) explicitly states that the investigator should have qualified staff and appropriate facilities and should only delegate tasks to individuals qualified by education, training, and experience. This was implied before; now it’s spelled out. The investigator must maintain a list of delegated tasks and who is authorized to perform them (the delegation log). Importantly, E6(R3) clarifies that routine duties that are part of normal clinical practice do not necessarily need to be listed as trial-specific delegation. For example, if a hospital phlebotomist draws blood as part of their regular job, the guideline indicates they may not need to be individually named on the delegation log for that routine task. This eases administrative burden – previously, some inspectors expected every person touching trial data be on the log. Now the focus is on those performing trial-specific activities that go beyond their routine care role.
• Oversight of Service Providers: New text in E6(R3) acknowledges that sponsors may contract third-party services (like central labs, ECG readers, home nursing services), but the investigator has the right and responsibility to judge the qualifications of those providers as well for the tasks affecting their patients. In practice, this means if a sponsor brings in, say, a mobile health company to do home visits, the investigator should be comfortable that this company’s personnel are capable. Investigators can request training or CVs from such providers. The guideline even says investigators “retain the final decision” on whether a service provider is appropriate. While in reality investigators might not reject a central vendor chosen by the sponsor, regulators want investigators to be in the loop and not abdicate oversight. In site inspections, an investigator might be asked how they ensured that a local lab used was certified – the expected answer could be that the sponsor provided lab certifications and the investigator reviewed/filed them, indicating active oversight.
• Medical Care and Decisions: Historically, GCP said that a qualified physician (or dentist, when applicable) should be responsible for trial-related medical decisions. This posed a challenge in some scenarios like nurse-led research or trials in allied health fields. E6(R3) expands this – it specifies that “healthcare professionals authorized by law” can oversee participant care. This means non-physician investigators (e.g., a PhD researcher, or a nurse practitioner) could be the principal investigator as long as medical decisions are covered by appropriate clinicians in the team. It grants flexibility: for example, a psychologist could lead a behavioral trial and still ensure patients’ general medical issues are handled by a study physician sub-investigator. The guiding principle is participants should always have qualified medical attention for trial-related health matters; E6(R3) doesn’t insist it must always be the PI if the PI isn’t an MD, but then the PI needs to delegate that responsibility clearly to someone who is qualified (and participants should be informed who to contact for medical concerns).
• Training of the Site Team: E6(R3) emphasizes that the investigator should ensure all personnel assisting in the trial are adequately trained for their specific roles – not just GCP training, but also protocol-specific tasks. Moreover, it says training should be proportional to the tasks: someone doing a novel procedure for the trial would need thorough training, whereas someone doing something they already do daily may not need much additional training. The delegation log or training log should reflect that key staff were trained in the protocol, use of any trial tools, and GCP refreshers if needed. The guideline also notes to document this training (via attendance logs, certificates, etc.). Practically, an investigator might hold a site initiation meeting for their team and cover all trial duties, then file the slides and attendee list as evidence – this is the kind of practice E6(R3) expects. It ensures, say, the lab technician doing an unusual assay was properly instructed, or the nurse administering an investigational infusion was trained on that procedure and recognizing its side effects, even if these tasks are within their general competency.

Informed Consent and Patient Communication

Investigators bear the responsibility for the informed consent process, even if they delegate parts of it. E6(R3) adds clarity here too:

• Identity Verification: When using electronic or remote consent, Section 2.8.1(e) reminds investigators to verify participants’ identity, particularly in remote scenarios. This is a practical addition – if a consent is done via a web portal, the investigator might need to confirm it’s indeed the correct person (perhaps by a phone call or verification of personal details). It’s part of ensuring the validity of consent.
• Ongoing Dialogue: While not new, it’s worth noting E6(R3) reaffirms that investigators should keep participants informed throughout the trial (e.g., new findings, results if appropriate after the trial). They should also be accessible to answer questions at any time during participation. This underscores the investigator’s role as the primary point of contact and advocate for participants.
• Handling Withdrawals: Investigators are now explicitly advised (Annex 1, 2.9.2) that if a participant expresses the desire to withdraw, the investigator or delegate should attempt to understand the participant’s concerns and inform them of options (like staying in follow-up only, etc.) without coercion. If a participant is unhappy or fearful, the investigator should ethically address it to see if the issue can be resolved. For example, a patient might want to quit because of a scheduling burden; the site could offer more flexible scheduling if that’s feasible. This guidance essentially encourages investigators to engage in compassionate problem-solving, but absolutely not to pressure someone to stay if they truly wish to leave. Any withdrawal and the participant’s stated reason (if given) should be documented by the investigator.

Delegation and Documentation

Delegation Log: Maintaining an up-to-date delegation log is a critical investigator responsibility. E6(R3) made a slight relaxation (not needing to list people performing purely routine clinical roles), but in practice, most sponsors and monitors will still expect a fairly detailed log. The log should list all key study staff at the site, their roles, and the dates they are authorized to start/stop those roles. The investigator should sign this log to acknowledge that delegation.

Investigators should keep the log current (e.g., if a new nurse joins mid-study, add them; if a coordinator leaves, note the end date of their involvement). It’s one of the first things inspectors review to see if everyone doing trial work was properly delegated and qualified. Investigators should also keep CVs and training certificates (GCP training, etc.) for each person on file to back up that they were qualified.

Final Accountability: A mantra to remember: delegation is not abdication. An investigator can delegate tasks but not responsibility. E6(R3) emphasizes that the investigator is responsible for oversight of those to whom tasks are delegated. This means, for instance, if sub-investigator Dr. X is seeing patients on some visits, the PI should have a mechanism to know how those visits went (perhaps regular meetings or review of notes). If a study coordinator is handling drug storage and dispensing, the PI should periodically check the drug accountability records.

One new point (Annex 1, 2.3.1) is that E6(R3) acknowledges sometimes sponsors or CROs directly provide certain site support services (like EDC entry personnel in some large trials). Even in those cases, the investigator should ensure those individuals are suitable and should only allow access to patient data if appropriate. Essentially, everyone working on trial data at that site, even if external, falls under the investigator’s purview in terms of ensuring confidentiality and correctness.

Medical Oversight and Safety Reporting

Investigators have primary responsibility for recognizing and reporting adverse events (AEs) and ensuring medical care for participants:

• Adverse Event Management: E6(R3) clarifies that the investigator should record all adverse events and intercurrent illnesses, including those that happen before the patient got the first dose of the investigational product if they are relevant (like a baseline medical event that might impact trial data). This nuance (Section 2.7.2a) reminds investigators not to ignore events just because they pre-date study treatment – for example, if a patient had a serious worsening of their condition after signing consent but before starting study drug, it should still be documented and reported as it may affect eligibility or outcomes.
• Serious Adverse Events (SAE) Reporting: As before, investigators must immediately report all SAEs to the sponsor (except those identified in the protocol as not needing immediate reporting, like some hospitalizations for disease progression in oncology trials). E6(R3) doesn’t change the timelines but re-emphasizes the need for prompt communication and follow-up reports. Investigators should also inform their ethics committee as per local requirements.
• Medical Decisions: Investigators should make trial-related medical decisions (or delegate to a sub-investigator physician when appropriate). For example, adjusting a dose for safety, deciding to pause treatment for a patient due to an AE, providing concomitant medications – these decisions need to be made by a qualified clinician on the study team. E6(R3) broadens who can be that clinician, but it must be documented who it is. In practice, if the PI is not a physician, typically a sub-investigator who is a physician will be designated for medical oversight. It’s wise then to have that person clearly identified on the delegation log as responsible for trial medical care decisions.
• Participant’s Personal Doctor: GCP since R2 has said participants’ primary physicians should be notified of their trial participation if the participant agrees. E6(R3) continues to support engaging personal healthcare providers. Investigators should ask the participant if they want their GP informed, and if yes, send a brief letter about the trial and study drug. It’s both courtesy and safety (so the GP doesn’t prescribe something that could conflict with the study). Document whether the participant agreed and the letter if sent. It’s a small duty that sometimes gets overlooked, but it reflects good patient care coordination.

Compliance and Preventing Deviations

Investigators are responsible for protocol compliance at the site. E6(R3) touches on a few items to bolster this:

• Feasibility & Protocol Understanding: Before a trial starts, investigators should assess protocol feasibility and clarify any uncertainties. E6(R3) Principle 8 highlights “clear, feasible protocols.” Investigators are partly the judge of feasibility – if something in the protocol is impractical at their site, they should communicate that to the sponsor. It’s better to address it upfront than end up with protocol deviations later. For instance, if the protocol required an MRI within 24 hours of each visit but the site’s MRI scheduling takes a week, that’s a flag to discuss with the sponsor/CRO. Perhaps the protocol can be amended or a deviation allowance made. Regulators would rather see a well-thought-out plan than numerous deviations because of poor planning.
• Avoiding Deviations: Despite best efforts, some deviations happen. E6(R3) encourages a preventive mindset: adequate training, patient reminders, and careful trial conduct should minimize missed visits, mis-dosed meds, etc. If a deviation occurs, investigators must document it and take appropriate action (e.g., retrain staff, counsel the participant, or in serious cases, consider removing a participant if safety or validity is compromised). Sponsors often have a protocol deviations log form that investigators fill. Promptly addressing the root cause of a deviation is part of the investigator’s quality management on site.
• Engaging with Monitoring: Monitors (CRAs) will visit or remotely review the site’s data. Investigators (and their coordinators) should engage actively with monitors, not see them as mere auditors. Monitors check data and processes and give feedback. If a monitor notes an error or something missing, investigators should correct it promptly and reflect on how to prevent it again. E6(R3) fosters a culture of continual improvement – an investigator should use monitoring findings to improve their site’s performance. Frequent issues (like late data entries or consent form errors) should be discussed with the study team and fixed systemically (maybe through re-training or process changes). Regulators love to see when a site took monitoring feedback seriously and improved over time.

Documentation by the Investigator

Beyond the delegation log and consent forms, investigators are also responsible for source documents accuracy and availability. E6(R3) doesn’t drastically change source documentation requirements but reinforces:

• All trial-related observations and data must be promptly recorded in source documents (medical records, clinic charts, etc.) and then accurately transcribed to case report forms (CRFs). If using electronic source, ensure it’s as reliable as paper would be.
• Corrections to source and CRF should be done per GCP (single-line strike through on paper with date/initial, or audit-trail tracked corrections in electronic systems, with explanation if not obvious).
• Investigators should sign off on key documents like the completed CRF casebook for each participant, attesting the data are complete and correct. Many EDC systems have an electronic PIN for PI sign-off on CRFs; investigators should do these in a timely manner, not wait until months after study end.

Conclusion: The Investigator as the Responsible Leader

ICH E6(R3) essentially reaffirms the investigator’s role as the captain of the ship at the site, with a capable crew (study staff) and tools (protocol, training) to navigate successfully. The updates encourage practicality (don’t over-document routine tasks) and inclusivity (allowing broader types of qualified investigators), but they also reinforce that the investigator’s judgment and oversight are irreplaceable.

For investigators, the key takeaways to meet E6(R3) expectations are:

• Maintain clear oversight of all trial activities at your site – know who is doing what, and make sure they do it right.
• Document your delegation and training thoroughly.
• Stay on top of data quality and participant safety: review data often, follow up on AEs, ensure protocol adherence, and act on any issues immediately.
• Communicate – with your team, with the sponsor/monitor, and with participants. Being proactive in communication prevents many problems.
• Be engaged and present as a leader: even if a coordinator handles day-to-day tasks, the PI should regularly meet with the study team, review progress, and personally see participants periodically if possible. This hands-on approach often distinguishes high-performing sites.

Investigators who fulfill these responsibilities not only comply with E6(R3) but typically run more successful trials – with better data, fewer errors, and safer, happier participants. Regulators, for their part, will look for evidence of this leadership and diligence in site records and during inspections. For example, an inspector might ask the PI, “How do you oversee the work of your sub-investigators and coordinators?” A strong answer referencing regular team meetings, co-signing of critical assessments, and oversight of data reports will demonstrate compliance with the spirit of E6(R3).

In summary, ICH E6(R3) provides investigators with clarity and even some relief on minor administrative burdens, but it also underscores that the investigator’s commitment to GCP principles must be unwavering. Through careful delegation, continuous oversight, and active management of their research team and patients, an investigator ensures that the trial not only follows the protocol but does so in a way that is ethical, safe, and scientifically reliable. The guideline supports investigators in this mission, making it clear that when investigators fulfill their responsibilities, the entire trial stands on solid ground.

References

• ICH Guideline for Good Clinical Practice E6(R3), Final Step-4 Guideline, Jan 6, 2025. [1]
• “The revamped Good Clinical Practice E6(R3) guideline: Profound changes in principles and practice,” Arun Bhatt, Perspectives in Clinical Research, 2023. [3]
• TransCelerate/ACRO’s E6(R3) Asset Library: tools on trial design, risk management, data governance. [5]

For those interested in gaining our Transcelerate Biopharma-certified courses, please enroll in our ICH GCP E6 R3 courses at https://www.whitehalltraining.com/

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Guidance To Explore

For those wanting to dive deeper into the details:

• ICH E6 (R3) Final Guideline (Step 4, January 6, 2025) – The official reference text.
• FDA Overview of ICH E6 (R3) – A clear outline of the changes and their implications.
• EMA Step 5 Guideline – European regulatory perspective on implementation.
• TransCelerate ICH E6 Asset Library – Practical tools and frameworks to support adoption (TransCelerate).