The principal investigator is the individual responsible for the conduct of a clinical trial at a site. Under ICH E6(R3) — the Good Clinical Practice guideline that came into effect on 23 July 2025 — the investigator’s obligations span every phase of a trial: from qualification and site readiness before the first participant is enrolled, through protocol execution, informed consent, delegation of duties, adverse event reporting, and maintenance of essential records after the last participant exits.
This guide covers what ICH E6(R3) requires of investigators conducting clinical trials, how E6(R3) differs from its predecessor in key areas, and what these obligations mean practically for site teams, research coordinators, and compliance reviewers.
Investigator Qualification and Site Requirements
Under ICH E6(R3), an investigator must be qualified by education, training, and experience to conduct the trial and must meet all the requirements specified by the applicable regulatory authority. Before enrolling any participant, the investigator must confirm that the site has adequate resources — including facilities, equipment, and staff — to conduct the trial properly for its anticipated duration.
The investigator must provide the sponsor with current, accurate information about their qualifications — including an updated curriculum vitae — and must inform the sponsor promptly of any changes that could affect their ability to conduct the trial.
Protocol Compliance and Deviation Management
The investigator agrees to conduct the trial in accordance with the approved protocol. Protocol changes require IRB/IEC review and sponsor agreement before implementation, except in urgent situations where a deviation is necessary to protect participant safety.
Any departure from the approved protocol, whether planned or unplanned, must be identified and documented at the time it occurs. The record must describe what happened, when, and why.
The sponsor must be notified of deviations according to the agreement. Deviations that affect participant safety or data integrity, or that constitute non-compliance with GCP, must also be reported to the IRB/IEC.
The investigator must assess whether the deviation affected participant safety or data integrity, implement corrective and preventive actions, and document both the assessment and the actions taken.
Informed Consent Obligations
Obtaining and documenting properly informed consent is one of the investigator’s most fundamental obligations. Under ICH E6(R3), consent must be freely given, obtained before any trial procedures are performed, and documented according to the approved process.
Delegation of Trial-Related Duties
The investigator may delegate specific trial-related activities to qualified members of the site team. However, delegation does not transfer the investigator’s ultimate responsibility for the conduct of the trial at the site.
Specific clinical, administrative, and data-entry tasks may be delegated to appropriately qualified team members: coordinators, nurses, sub-investigators, pharmacists, and data managers as appropriate to their qualifications and the task.
The investigator’s overall responsibility for site conduct cannot be delegated. Medical decisions about participant eligibility, continuation, and management of adverse events require medical judgment and cannot be assigned to non-medical personnel.
The Delegation of Authority log (or signature and delegation log) must document every person to whom duties have been delegated, the specific tasks delegated, and the period of delegation. This log must be current and signed by the investigator. Undocumented delegation is a GCP finding: if a task is performed by someone not listed on the delegation log, it constitutes a deviation regardless of whether the person was qualified to perform it.
In site qualification visits and regulatory inspections, delegation log gaps are among the most consistently identified findings. Common patterns include: tasks performed during study periods not covered by the log, staff who left and were replaced without the log being updated, and coordinators performing eligibility assessments that required medical sign-off not documented on the log. A quarterly delegation log review against actual task performance records is a reliable prevention measure.
Adverse Event and Safety Reporting
The investigator is responsible for identifying, assessing, and reporting adverse events (AEs) and serious adverse events (SAEs) according to the protocol, ICH E6(R3), and applicable regulatory requirements. The investigator’s obligations in safety reporting are distinct from those of the sponsor.
The investigator must make a clinical assessment of the causal relationship between the investigational product and any serious adverse event. This causality assessment — whether the event is considered related or unrelated to the investigational product — is the investigator’s medical judgment and must be documented. The sponsor may independently assess causality, but the investigator’s assessment must be recorded regardless.
Investigational Product Accountability
The investigator is responsible for the investigational product at the site. This includes receiving, storing, dispensing, and returning or disposing of the product according to the protocol and sponsor instructions.
Essential Records and the Investigator Site File
The Investigator Site File (ISF) — also called the Trial Master File at the site level — must contain all essential documents defined in ICH E6(R3) Annex 1. These documents demonstrate that the trial was conducted in accordance with GCP and applicable regulatory requirements.
Key Changes Under ICH E6(R3)
ICH E6(R3) introduces several significant changes that directly affect investigators’ obligations compared to E6(R2).
E6(R3) introduces a risk-proportionate framework. Oversight activities and documentation requirements should be calibrated to the risk level of the trial — lower-risk trials require proportionately less intensive monitoring, but the investigator’s core obligations remain.
E6(R3) introduces the concept of identifying critical-to-quality factors prospectively, before the trial starts. Investigators and site teams should understand which data points and processes are critical to the trial’s conclusions and focus quality efforts there.
Section 4 of E6(R3) adds an explicit data governance section. Investigators must ensure that data collected at the site are accurate, complete, legible, and attributable — consistent with ALCOA+ principles — and that source data are accessible for verification.
Draft Annex 2 of E6(R3) provides guidance for decentralised, pragmatic, and real-world trials. Investigators conducting remote visits, telemedicine consultations, or digital data collection must ensure these processes meet GCP standards.
Frequently Asked Questions
Yes, if the coordinator is appropriately trained, listed on the delegation log for that task, and the IRB/IEC has approved this practice for the study. The investigator retains responsibility for ensuring the consent process is properly conducted, regardless of who performs the discussion.
This is a major protocol deviation. The investigator must document it, notify the sponsor and IRB/IEC, assess the impact on participant safety and data integrity, and implement corrective actions. Depending on the severity, the sponsor may need to notify the regulatory authority. Repeated eligibility deviations are a serious GCP finding that can result in inspection of all data from the site.
ICH guidelines are not directly legally binding, but regulatory authorities in ICH member regions (FDA, EMA, PMDA, Health Canada) implement GCP requirements through their own regulations and guidance. Clinical trials intended for regulatory submission are conducted to E6(R3) because data generated outside GCP standards may not be accepted in marketing authorisation applications. In practice, E6(R3) compliance is required for any trial generating data intended for regulatory use.
ICH E6(R3) requires essential records to be retained for a minimum of 15 years after trial completion, or for 2 years after the last marketing authorisation granted in an ICH member region, whichever is longer. Local regulations may specify longer periods. The investigator must not destroy records without prior written agreement from the sponsor, and must notify the sponsor if retention at the site becomes impossible.
Related Resources
- ICH E6(R3): Guideline for Good Clinical Practice (Step 4, January 2025)
- FDA, “Good Clinical Practice: Consolidated Guideline E6(R2)”
- EMA, ICH E6 Good Clinical Practice — Scientific Guideline
- A practice test covering GCP/ICH obligations of investigators and sponsors is available in the Practice Tests section.
Sources
- ICH, “E6(R3) Guideline for Good Clinical Practice Step 4” (January 2025)
- EMA, “ICH E6 Good Clinical Practice: Scientific Guideline”
- Clinical Trials Toolkit UK, “Summary of Key Changes in ICH E6(R3)” (March 2026)
- FDA, “ICH E6(R2) Good Clinical Practice Guidance”
- MRCT Center, “ICH GCP E6(R3) Response” (2023)