Clinical Trial Quality and Compliance Update


Applied Clinical Trials

The topic of clinical trial quality and compliance continues to evolve in clinical operations, based on discussions at ExL’s 9th Proactive GCP Compliance Conference.

The intriguing topic of clinical trial quality and compliance continues to evolve in clinical operations, based on discussions at ExL’s 9th Proactive GCP Compliance Conference. The biopharmaceutical industry is starting to act on implementing the ICH-E6 R2 guideline, experts discuss the importance of culture and how it influences compliance, and seasoned industry professionals elaborated on their experiences with inspection readiness. ExL’s 9th Clinical Quality Oversight Forum is occurring in Philadelphia October 10-12, 2018.

Risk Management Evolution After ICH-E6 R2

Jonathan Rowe, Executive Director and head of Clinical Development Quality Performance and Risk Management at Pfizer, discussed the evolution of clinical trial risk management prior to and post ICH-E6 R2. In its early evolution (around 2011), lacking GCP guidelines on risk management forced biopharmaceutical enterprises to rely on internal SOPs that require the collection and reporting of risks that impacted the safety, rights and well-being of trial participants, and study data integrity. However, this resulted in collecting and reporting on every new quality event, which complicated quality operations, and was resource exhaustive. Risk management, then, matured (around 2015) into using collected risk data from previous studies to generate predictive models, and categorizing factors that posed the highest risks towards GCP quality issues. This enabled study teams and vendors to improve decisions by focusing resources on risks that that had a critical impact, and process owners could adapt their processes on predicted risk levels (i.e., creating RBM plans, etc.). This ultimately allowed R&D organizations to predict risk rates for specific risk categories (i.e., significant quality events, protocol deviations, and protocol amendments) during the study development phase. Now, with the release of ICH-E6 R2, quality management is more connected with the clinical study report through risk control and risk reporting guidelines. Specifically, tolerance limits need to be established during the planning phase of a trial, and deviations from those tolerance limits require predefined policies to address what mitigations and actions will need to be taken. The benefits of defining, planning, documenting, managing, and reporting risk enables study teams to not only enhance subject protection and study data integrity, but also improve the risk management process.

A Culture of Compliance

TransCelerate’s QMS initiative’s emphasis on creating a culture of compliance, and how doing so can promote organizational behaviors that support clinical quality appeared to have resonated at this event. Catherine Arthey of DArcy Consulting indicated that signs of a compliance culture include alignment with strategic goals, idealistic leadership by senior managers, robust training and education, and incentivization and reinforcement of good behavior; Arthey explained this results in a reduction of misconduct, employees protecting organizational integrity and quality by voicing concerns, and enhanced employee performance. Additionally, Arthey illustrated several stages of organizational compliance maturity including reactivity, enforcement, awareness, control, and

enablement. In the reactive phase, organizations tend to be incident-driven, where problems cause setbacks and organizations are constantly fighting fires. In the enforcement phase, organizations tend to be audit-driven, as there is quality governance, CAPA implementation, and segregation between operations and compliance. In the awareness phase, companies are metrics-driven, as processes start to harmonize, there are active CAPA processes, and quality-driven process improvement. In the controlled phase, enterprises tend to be risk-driven, as interactive compliance management controls exist, and active risk management becomes implemented (most likely with the use of technology). Lastly, companies in the performance-driven phase tend to drive quality and compliance through business performance, compliance becomes an essential part of clinical operations, and the compliance group proactively becomes a mentoring entity.

Inspection Readiness

There was coverage on inspection readiness pertaining to the Trial Master File (TMF). Karen Fried, Essential Document Lead at Merck, indicated that TMF inspection readiness means that sponsors and CROS must ensure that the TMF is complete, contains all essential documents that are properly filed, and that there is no indication of missing documentation. Fried explained that regulatory authorities inspect TMFs for complete documentation, clear processes, contemporaneous filing, clearly defined TMF locations, and demonstrate compliance. The consequences of poor TMF maintenance include halting the study, fines, and compromising patient safety and wellbeing. Common inspection findings include missing pages, misfiled documents, duplicates, inaccuracies, incomplete documents, discrepancies, gaps, and lack of vendor oversight. Fried made suggestions including developing an action plan that establishes a TMF at the beginning of a trial, planning regular monitoring cycles, developing a master list of expected TMF documents, and leveraging QC processes and tools throughout the study.


In summary, updated industry guidance documents are starting to shape execution principles of clinical quality, and the conceptualization and adoption of organizational principles, such as culture, theoretically influence every decision employees make towards organizational performance-and that includes quality and compliance. Additionally, quality managers appear to be evangelizing the importance of inspection readiness, meaning that studies should be prepared with the assumption that an inspection can happen at any time.


Moe Alsumidaie, MBA, MSF is Chief Data Scientist at Annex Clinical, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.

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