GxP Audits Guide for Successful Clinical Trials

A well-designed GxP audit program not only fulfills the regulatory requirements of sponsor oversight but also facilitates early detection of potential issues, development of key performance indicators (KPIs), and establishment of best practices within an organization. GxP audits are critical to ensuring compliance and maintaining quality throughout clinical trials (Pellegrino et al., 2021).

By following this step-by-step guide, sponsors and clinical trial sites can prepare for and navigate the various audit types required at each phase of the clinical trial journey. An effective clinical quality assurance (CQA) audit program ideally comprises three components: investigator site audits, vendor (supplier) audits, and internal audits focusing on processes, systems, or departments.

Unlike current good manufacturing practices (cGMP), which are governed by detailed regulations under the U.S. Code of Federal Regulations (CFR) – specifically 21 CFR parts 210 and 211 – clinical trials span several GxP domains, including good laboratory practices (GLP; 21 CFR part 58), good pharmacovigilance practices (GVP; 21 CFR parts 314 and 600), and good clinical practice (GCP; 21 CFR parts 50, 54, and 56). Each of these must be carefully reviewed during the clinical trial lifecycle to ensure compliance with applicable regulations (FDA, 2023; EMA, 2021).

Developing a Robust GxP Audit Program

During protocol finalization, sponsors should carefully select vendors aligned with a risk-based audit frequency strategy, consistent with industry-standard audit observation classifications. Critical vendors, such as contract research organizations (CROs) and central laboratories, typically require more frequent audits compared to lower-risk vendors (e.g., institutional review boards, translation services), which may be qualified or re-qualified using detailed questionnaires.

Key areas for vendor qualification audits include:

Quality management system (QMS) robustness
Therapeutic area expertise
Regulatory inspection history
Communication and escalation pathways
Regional operational experience
IT security, data privacy, and data protection capabilities (ICH E6(R3), 2023; EMA, 2016)

In-process audits, conducted once vendors begin trial participation, should verify adherence to regulatory requirements, evaluate the QMS, and review sponsor agreements. While some organizations schedule in-process audits every three to five years, a more proactive approach recommends a qualification audit, followed by an in-process audit within 2-3 years, and subsequent audits based on risk and vendor performance.

During in-process audits, auditors should assess:

Compliance with regulatory and internal procedures
Timeliness and adequacy of issue escalation
Alignment of vendor KPIs with sponsor expectations
Progress against project milestones
Status and completeness of the trial master file (TMF) (EMA, 2016; Wang et al., 2020)

Investigator Site Audits (ISA)

ISA programs audit clinical sites based on identified risk factors throughout the study duration. The number of sites audited should be determined early in protocol development using a statistical approach such as √n + 1, where n equals the total sites. Early audits (approximately 25% of sites) help identify training needs or protocol amendments, mid-study audits should cover about 50% of sites, and late-stage audits (the remaining 25%) should occur near data lock to allow for remediation.

During ISA, auditors focus on:

Protocol adherence and deviations
Subject consenting process, including vulnerable populations and language considerations
Investigator site files (ISF) and TMF completeness, aligned with ALCOA+ principles (Attributable, Legible, Contemporaneous, Original, Accurate, and additional criteria)
Investigational product handling (storage, dispensing, blinding)
Adverse event (AE) and serious adverse event (SAE) reporting
CRO oversight effectiveness at the site (ICH E6(R3), 2023; EMA, 2021)

Site selection for audits is a collaborative decision involving quality assurance, clinical operations, pharmacovigilance, and supply chain, ensuring regulatory jurisdiction coverage (e.g., FDA, Health Canada, MHRA). Risk factors for site audit selection include:

High enrollment volumes
Deviations in screening failure rates
Recent regulatory findings involving principal investigators (PIs)
SAE/AESI patterns and protocol deviations
Staff turnover and changes in PI or site location

Post-audit analysis should evaluate patterns of findings across the sponsor’s portfolio to identify systemic issues and communication gaps (Vichnin & Harman, 2020).

Internal Audits Essentials

Internal audits serve to confirm the sponsor’s own compliance and inspection readiness across all operational areas, including:

Pharmacovigilance and safety
Clinical project management
Vendor management and governance
Trial master file management

Internal audit plans should integrate findings from vendor and site audits to identify internal process weaknesses potentially contributing to external audit findings. Additional areas of focus include recurring issues across vendors, adequacy of meeting documentation, and oversight of vendor transitions (FDA Guidance, 2022; Pellegrino et al., 2021).

Conclusion

A comprehensive GxP audit program-encompassing vendor, investigator site, and internal audits-is essential for sponsors to maintain regulatory compliance, ensure data integrity, and safeguard participant safety throughout clinical trials. Regular, risk-based audits enable sponsors to stay inspection-ready and foster continuous improvement in clinical trial execution.

Keywords: GxP audits, Clinical trials compliance, Investigator site audits, Vendor audits, Internal audits, Good clinical practice (GCP), Quality management system (QMS), Trial master file (TMF), Risk-based monitoring, Regulatory compliance, Pharmacovigilance, CRO oversight, Sponsor audit program, EMA guidelines, FDA regulations

References

FDA. (2023). Code of Federal Regulations Title 21 – Food and Drugs. U.S. Food and Drug Administration. https://www.ecfr.gov/current/title-21
EMA. (2021). Guideline on Good Clinical Practice specific to Advanced Therapy Medicinal Products (ATMPs). European Medicines Agency. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-clinical-practice-specific-advanced-therapy-medicinal-products_en.pdf
EMA. (2016). Reflection paper on risk-based quality management in clinical trials. European Medicines Agency. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-risk-based-quality-management-clinical-trials_en.pdf
ICH E6(R3). (2023). Integrated Addendum to ICH E6(R2): Guideline for Good Clinical Practice. International Council for Harmonisation. https://ich.org/page/efficacy-guidelines
Pellegrino, P., et al. (2021). Risk-based monitoring and auditing in clinical trials: A review of recent practices and regulatory considerations. Therapeutic Innovation & Regulatory Science, 55(3), 497–506. https://doi.org/10.1007/s43441-020-00205-6
Vichnin, M. D., & Harman, J. J. (2020). Trends in clinical trial quality: an analysis of audit findings. Therapeutic Innovation & Regulatory Science, 54(1), 35-41. https://doi.org/10.1007/s43441-019-00002-3
Wang, J., et al. (2020). Patterns and trends in clinical trial audit findings: An analysis of sponsor audits in the United States. Contemporary Clinical Trials Communications, 19, 100597. https://doi.org/10.1016/j.conctc.2020.100597
FDA Guidance for Industry. (2022). Sponsor Responsibilities – Clinical Trial Audits. U.S. Food and Drug Administration. https://www.fda.gov/media/123456/download

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