Clinical QA Programs under ICH E6(R3)

Clinical Trial Quality Assurance requirements are set to change dramatically, driven by widespread global regulatory convergence. This sets a new harmonized standard for trial inspection, conduct, and oversight.

Last year, the International Council of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) released ICH E6 (R3). Over the past 12 months, major government agencies in the US, Europe, the UK, Japan, Canada, and China have moved rapidly to adopt the ICH E6(R3) as a harmonized global standard for Good Clinical Practice (GCP).

This is a call to action to address concerns about industry adoption of key principles in quality and risk management. A 2023 study by the Tufts Center for the Study of Drug Development found that only 43% of clinical trials had no Risk-Based Quality Management components. The study noted systemic barriers among clinical trial sponsors, such as a lack of awareness and an aversion to change. With international regulators aligning on stricter standards, they're signaling that this will not be acceptable going forward.

This is particularly relevant to drug-device co-development trials. In Vitro Diagnostics (IVD) and Companion Diagnostics (CDx) sponsors have a special imperative to anticipate ICH E6(R3)-related changes, since assay validation, sample collections, and biomarker data are integral to overall trial conduct.

Quality by Design

The ICH E6(R3) makes a conceptual leap from compliance-by-procedures to a design-oriented approach. Static Standard Operating Procedures (SOPs) are replaced with a philosophy of living governance that "incorporates flexible, risk-based approaches and embraces innovations in trial design, conduct, and technology," according to the FDA. The FDA explicitly notes that prior E6(R2) guidance was criticized for its "one-size-fits-all approach to clinical trials."

Quality design explicitly requires sponsors to identify Critical-to-Quality (CtQ) factors early in trial planning. These are factors that directly impact participant safety and data reliability. In another example of regulatory affirmation, Health Canada's implementation notice explicitly states: "Health Canada expects sponsors to clearly identify Critical to Quality Factors with their associated risks and mitigation measures in their protocols."

Inspection Readiness 

In the United Kingdom (UK), the Medicines and Health Products Regulatory Agency’s (MHRA’s) December 2025 GCP updates are a reflection of the new E6(R3) expectation. “Sponsors are reminded to maintain continuous inspection readiness, with structured documentation and clear evidence of compliance with core GCP principles." This is driving the increasing demand for “mock inspections” that run against E6(R3) principles. The FDA’s BIMO program data reflects the importance of constant readiness and persistent failure by a significant portion of sponsors who received notices of deficiency. The agency cited a pattern of unprepared sponsors, citing structural problems with nearly a quarter of all inspections for nearly a decade. As a recent example, in 2024, the agency inspected 125 sponsors, and approximately 25% received an FDA Form 483 Notice of Inspectional Observations. A key part of readiness is the Trial Master File (TMF). The FDA's December 2025 consolidated BIMO inspection guidance update makes electronic records access now statutory, not advisory. FDA must have read-only access upon arrival with no setup time. Remote Regulatory Assessments (RRAs) are now formal oversight instruments. Sponsors must treat every remote records request with the same rigor as an on-site inspection. “The Trial Master File should show how quality is managed in an ongoing manner, not only when an inspection is looming,” according to an expert panel at last year’s Trial Interactive conference in London. “The TMF becomes a living record of how systems support the trial rather than a static store of documents.* Under E6(R3), the TMF is expected to show that decisions were made with intention, that service providers were guided by clear controls, and that evidence of review exists.

Vendor Oversight

Accountability is unequivocal in ICH E6(R3). Trial sponsors are responsible for any delegated activities, including quality, safety, and data integrity across all vendors and partners. E6(R3) is far more precise and stringent in defining oversight obligations than its predecessor.

This is another well-documented gap that the new guidance intends to close, related to the prior on inspection readiness example above. Studies such as this 2024 Risk-Based Quality Management Working Group report have found that centralized monitoring systems for visibility over vendor and site performance have been underutilized in the past.

For CDx sponsors, a typical list of trial sponsors might include a central laboratory, tissue or biopsy sample logistics, pathology review, EDC systems, device validation partners, and a CRO for clinical management.

Global Impact

ICH E6(R3) foundation is built upon introducing more flexible risk-based and technology-driven frameworks intended to improve efficiency and align with the growing complexity of clinical trials. The harmonized nature of ICH means E6(R3) will automatically influence regulatory inspections and industry practices in ICH member countries such as the US, EU, Japan, Singapore, Switzerland, and Canada. Sponsors running ex-US trials cannot manage this as a US-only compliance exercise.

FDA (US): Final guidance issued September 2025 explicitly aligns with ICH principles and announces the agency's expectation of Quality by Design (QbD), Risk Based Quality Management (RBQM), and proportionate oversight in all sponsored trials.

European Medicines Agency (EMA): Principles and Annex 1 in effect since July 2025.

MHRA (UK): Phased rollout from December 2025 through 2026.

Health Canada: In effect as of April 2026 with a 6-month transition period. Implementation aligned with EMA, FDA, and Japan.

PMDA (Japan): Published the E6(R3) guideline document for adoption, consistent with Japan's standing as an ICH member committed to harmonization.

CDE and NMPA (China). China’s Center for Drug Evaluation has released a public proposal to adopt E6(R3) principles in 2026 for all new clinical trials. Regulators have also issued major reforms of Good Clinical Practices, including a new standalone chapter on Data Governance. The new proposals also explicitly recommend E6(R3) staples like Quality by Design, risk-proportionate oversight, and electronic audit trails.

Landrich has supported In Vitro Diagnostics/Companion Diagnostics clients through BIMO inspections, mock audit exercises, vendor qualifications, and gap assessments in the US and internationally. Contact us to assess your E6(R3) readiness.