ICH E6(R3) and clinical investigator selection: what it asks of sponsors
ICH E6(R3) is the 2025 revision of the international Good Clinical Practice guideline. For clinical investigator selection it keeps the sponsor’s core duty — choose clinical investigators qualified by education, training and experience, with the resources to run the trial — and makes that choice part of the sponsor’s oversight of the trial: something to plan, document, and act on when a site falls short.
What E6(R3) is, and what binds in the United States
The International Council for Harmonisation adopted E6(R3) in January 2025. It took effect in the European Union on 23 July 2025, and FDA published it as final guidance in September 2025. It replaces E6(R2) and reorganizes the guideline around principles, risk-proportionate quality management and oversight, rather than around checklists.
In the United States, guidance is a recommendation. What binds a drug or biologic trial is the Code of Federal Regulations, and for selection that is 21 CFR 312.53: the sponsor “shall select only investigators qualified by training and experience as appropriate experts to investigate the drug.” When an FDA inspector records a finding, it cites a regulation, not E6(R3). The two point the same way, and sponsors that run trials in more than one region work to both. See Good Clinical Practice basics for how the guideline and the regulations relate.
What E6(R3) says about selecting clinical investigators
None of this is new in substance; E6(R2) asked much the same. What the revision changes is where selection sits: see clinical investigator selection for the criteria sponsors use in practice, and the site qualification visit for how the confirmation is usually done.
Selection is now part of the sponsor’s oversight
E6(R3) gives sponsor oversight its own section (3.9) and places selection inside it: “The selection and oversight of investigators and service providers are fundamental features of the oversight process” (section 3.9.5). The same section asks that oversight be fit for purpose and tailored to the complexity and risks of the trial, and that it include quality assurance and quality control of what clinical investigators and service providers do.
Behind it is one of the guideline’s principles (principle 10): a sponsor may transfer activities to others, but it retains overall responsibility for them, and for the quality and integrity of the trial data. A sponsor cannot hand the choice of sites to someone else and with it the consequences of a poor choice.
Documenting the selection
E6(R3) treats the selection as something an inspector or auditor should be able to reconstruct. Appendix C, on essential records, counts among them records that document “sponsor oversight of investigator site selection” (C.3.2(r)). Its table of essential records lists, as records that should generally be in place before the trial starts, the documents evidencing the clinical investigators’ qualifications (such as the curriculum vitae) and the site-selection monitoring report.
In practice that is the site-selection file: the qualification visit report, the evidence of qualifications, the record check with its date, and the selection decision, kept together. It answers the question an inspector asks: how did the sponsor know this clinical investigator was qualified? Clinical investigator vetting produces the record part of that file.
When a CRO selects the sites
Many sponsors transfer site selection to a contract research organization. E6(R3) calls a CRO, and anyone else doing trial work for the sponsor, a service provider, and keeps the sponsor responsible for it. The sponsor assesses the service provider’s suitability before selecting it (section 3.6.7), should have access to relevant information such as its procedures and performance metrics (section 3.6.8), and oversees the trial activities transferred to it, including any it subcontracts (section 3.6.9). Appendix C adds the documentation of how service providers were selected, assessed and overseen to the essential records.
So when a CRO proposes the sites, the sponsor still owns the oversight of how they were chosen. The CRO’s own FDA record is part of that picture too: CROs and sponsors are inspected under the same program as clinical investigators. See sponsor responsibilities for clinical investigators for the US duties when obligations are transferred.
When a selected site falls short
Selection is not the end of the sponsor’s duty. Under section 3.12, noncompliance by a clinical investigator should lead to appropriate and proportionate action by the sponsor to secure compliance. Where noncompliance significantly affects, or could significantly affect, participants or the reliability of the results, the sponsor should find the root cause, put corrective and preventive actions in place and confirm they work, and notify the regulator or IRB where required. If significant noncompliance persists despite remediation, the sponsor should consider ending the site’s participation and notify the regulator and IRB as appropriate.
A sponsor learns of some of that noncompliance from its own monitoring. It does not always learn of FDA’s: FDA sends inspection findings to the clinical investigator, not typically to the sponsor. What follows an inspection, and who is told at each step, is in what happens after a BIMO inspection.
Where the FDA inspection record fits
E6(R3) does not say what evidence a sponsor must gather about a candidate, and it does not mention FDA inspection history. It asks the sponsor to select qualified clinical investigators, to oversee them, and to document both. A clinical investigator’s regulatory history is part of that qualification question, and the FDA record is evidence a sponsor can put in the file.
The check many selections run is for warning letters, disqualification and debarment. Those are the rare endings; the inspection history is everything before them, and it is where most of the information is: the inspections, the classification FDA assigned to each, and the findings it cited. Reading it is best done before the site qualification visit, so that the visit can ask about what the record shows. See clinical investigator inspection history for how to read one, and OAI, VAI and NAI for what each classification means.
Oversight continues after selection. A clinical investigator can be inspected, classified or sent a warning letter while running a trial for you, and a sponsor that watches the record learns of it from the record rather than from the site.
Questions this page answers
What is ICH E6(R3)?
It is the third revision of ICH E6, the international guideline for Good Clinical Practice. ICH adopted it in January 2025; it took effect in the European Union on 23 July 2025, and FDA published it as final guidance in September 2025. It replaces E6(R2) and is built around principles, risk-proportionate quality management and sponsor and investigator oversight.
Does ICH E6(R3) apply to trials in the United States?
FDA has published it as guidance, and guidance is a recommendation. The binding requirements for drug and biologic trials are in the Code of Federal Regulations; for selection, 21 CFR 312.53 requires the sponsor to select only clinical investigators qualified by training and experience. FDA findings cite the regulations. Sponsors running trials in more than one region generally work to both.
What does ICH E6(R3) require when selecting a clinical investigator?
The sponsor selects the clinical investigators, each qualified by education, training and experience and able to demonstrate adequate resources and facilities (section 3.7.1); the site’s qualifications, resources and facilities are confirmed as part of monitoring (section 3.11.4.5.2); and selection is treated as part of the sponsor’s oversight, which the guideline calls a fundamental feature of the oversight process (section 3.9.5).
Does ICH E6(R3) require checking a clinical investigator’s FDA inspection history?
It does not name sources of evidence. It asks the sponsor to select qualified clinical investigators and to document its oversight of site selection. A clinical investigator’s FDA record — inspections, classifications, findings, warning letters, and the disqualification and debarment lists — is evidence a sponsor can use for that, and FDA sends inspection findings to the clinical investigator, not typically to the sponsor.
What belongs in the site-selection file under ICH E6(R3)?
Appendix C counts records documenting sponsor oversight of investigator site selection as essential records, and lists the evidence of the clinical investigators’ qualifications and the site-selection monitoring report among the records that should generally be in place before the trial starts. In practice: the qualification visit report, the qualifications, the FDA record check with its date, and the selection decision.
Related: clinical investigator selection · clinical investigator vetting · site qualification visit · sponsor responsibilities · Good Clinical Practice basics · inspection history