Quality Assurance (QA) in Clinical Development has undergone significant changes over the past two decades. The US Code of Federal Regulations (CFR) initially did not explicitly mandate a system for managing quality throughout all stages of the clinical trial process.
However, the development of the FDA’s Bioresearch Monitoring (BIMO) Program and subsequent international guidelines has transformed the landscape of Good Clinical Practice (GCP) regulations. In this blog post, we will explore the evolution of GCP Quality and Compliance roles and their importance in ensuring the integrity and safety of clinical trials.
The Birth of GCP Quality Assurance
The FDA’s BIMO Program was established in response to Congressional Hearings in 1975 and 1976. It aimed to monitor all aspects of FDA-regulated research and led to the presentation of BIMO Inspection 483 observations and findings. These findings, along with Warning Letters issued to various stakeholders, set important compliance precedents that defined the “current” requirements in Good Clinical Practice (cGCP).
The BIMO Program targeted three main stakeholders: Sponsors/Contract Research Organizations (CROs)/Monitors, Institutional Review Boards (IRBs), and Clinical Investigators. Through on-site inspections and data audits, the FDA ensured the proper conduct and reporting of FDA-regulated research. As the BIMO Program progressed, it began to influence the concept of “current” Good Clinical Practice.
Evolution of GCP: ICH E6 Revision 1
In 1996, a collaborative effort by experts from Japan, the EU, and the US led to the approval of the ICH E6 Good Clinical Practice Revision 1—this international guideline standardized ethical and scientific quality standards for clinical trials involving human subjects.
A significant change introduced by ICH E6 Revision 1 was the requirement for a Sponsor Quality Assurance and Quality Control system, even when clinical operations were outsourced to Contract Research Organizations (CROs). This emphasized the Sponsor’s responsibility for maintaining quality throughout the trial.
Under ICH E6 Revision 1 Section 5.1, the Sponsor was mandated to implement and maintain quality assurance and quality control systems with written Standard Operating Procedures (SOPs) to ensure trials were conducted and data were generated, documented, and reported in compliance with the protocol, GCP, and applicable regulatory requirements. The Sponsor’s ultimate responsibility for the quality and integrity of the trial data was highlighted, even when key responsibilities were transferred to a CRO.
Further Advancements: ICH E6 Revision 2
In 2016, ICH E6 was revised again with the introduction of ICH E6 Revision 2. This was a transformational moment for GCP Quality Assurance. The revision emphasized the need for a risk-based approach to managing quality throughout all stages of the clinical trial process.
It brought forth additional requirements for a Quality System, Risk Management Plan, and other quality control measures. This shift required the industry to acquire new resources, capabilities, and competencies to meet the enhanced GCP requirements.
Under ICH E6 Revision 2 Section 5, the Sponsor must implement a system to manage quality throughout all stages of the trial process. This system should focus on essential trial activities that ensure human subject protection and the reliability of trial results.
The Sponsor is responsible for developing efficient clinical trial protocols, tools, and data collection and processing procedures. Additionally, the system should use a risk-based approach to identify, evaluate, control, communicate, review, and report risks. All these elements are to be documented in a formal Risk Management Plan.
The Risk Management Plan requires critical process and data identification, risk evaluation, risk control, risk communication, risk review, and risk reporting. This approach helps ensure that the methods used to assure and control the quality of the trial are proportionate to the risks inherent in the trial and the importance of the information collected.
Expanding Responsibilities of GCP QA
The evolving role of GCP Quality Assurance has seen a significant increase in responsibilities. Apart from reviewing essential trial documents for compliance, GCP QA is now responsible for ensuring the Informed Consent Form and Protocol reduce user error, managing risk, conducting periodic audits, and reporting quality and compliance metrics.
GCP QA also plays a critical role in preparing for FDA Bioresearch Monitoring Sponsor Inspections, ensuring the trial’s adherence to GCP throughout the study.
GCP QA is responsible for reviewing the protocol, risk management plan, oversight, monitoring plans, informed consent forms, and other essential documents referenced in ICH E6 Revision 2 Section 8.0 Essential Documents. The aim is to check for compliance with CFR and ICH E6 Revision 2 and to identify inconsistencies and problematic wording that could lead to protocol violations or deviations.
Another crucial responsibility of GCP QA is to provide recommendations on the Informed Consent Form and Protocol to reduce “user error” during the informed consent process and throughout the execution of the trial.
By focusing on prevention through a “quality engineer” approach, GCP QA aims to address the top reasons for FDA Bioresearch Monitoring Inspection 483 Observations, which often include inadequate Sponsor oversight of the trial and issues related to trial data integrity and adherence to the investigation plan and protocol.
GCP QA also collaborates with various stakeholders to ensure quality and compliance throughout the trial. They work with Clinical Operations to review monitoring reports of site visits, with Regulatory Affairs to report compliance metrics, and with Medical Safety to implement risk management plans.
Periodic internal audits of Clinical Operations, Regulatory Affairs, Clinical Development, and Medical Safety are conducted to ensure compliance with current Good Clinical Practices and Safety Reporting Requirements.
Importantly, GCP QA is crucial in preparing for and leading FDA Bioresearch Monitoring Sponsor Inspections. By ensuring that the CRO and Clinical Trial Sites are ready for these inspections, GCP QA contributes to maintaining the integrity and compliance of the trial.
Importance of ICH E6 Revision 2 Compliance
While compliance with US 21CFR regulations is essential, more is needed to ensure GCP compliance. Numerous FDA 483 observations from the late 1990s were directly linked to non-compliance with ICH E6 Revision 1. As the research landscape evolves, companies must align with the ICH E6 Revision 2 guidelines to maintain effective GCP compliance.
By adopting a risk-based approach, implementing a robust Quality System, and embracing the expanded responsibilities of GCP QA, companies can enhance the quality and integrity of clinical trials. Compliance with ICH E6 Revision 2 helps protect human subjects, ensures reliable trial results, and fosters mutual acceptance of clinical data by regulatory authorities across jurisdictions.
Conclusion
GCP Quality and Compliance roles have come a long way since the inception of the FDA’s BIMO Program. Implementing ICH E6 Revision 1 and Revision 2 guidelines has reshaped the way clinical trials are conducted, emphasizing the importance of a risk-based approach and robust Quality Systems. Companies must recognize the changing landscape and redefine their roles and responsibilities to align with the evolving GCP standards.
By adhering to these guidelines, we can ensure the reliability, safety, and integrity of clinical trials for the benefit of human subjects and scientific progress. Embracing the advancements in GCP Quality Assurance will ultimately lead to improved patient safety, data integrity, and the advancement of medical research.
