Consideration of ICH Guideline, Industry Norms Necessary for Compliant Clinical Quality Assurance Plan

Savvy companies already understand that Quality Assurance (QA) must be integrated into the clinical development system, not relegated to an afterthought of audits and quality control (QC) checks. But exactly how should this be accomplished? Review of current international guidelines and current industry practices indicates that while few to no new responsibilities have been added, some have shifted. For instance, some activities traditionally performed by the trial manager may now be more appropriately assigned to the Good Clinical Practice (GCP) QA system.

Understanding these nuances is critical to compliance for new medical product sponsors. Inadequate sponsor oversight to ensure the integrity of data generated during the trial is one of the top two reasons for Bioresearch Monitoring (BIMO) Form 483 observations. Failure to adhere to the investigational plan and protocol—a role often considered specific to QA—is the other top reason for observations. An integrated approach to QA and Good Clinical Practice (GCP) is a new product sponsor’s best hedge against receiving those observations when the FDA inspects its clinical trial operations.

A review of recent industry trade association and global health authority presentations from the UK, US, Canada and Australia show how expectations for how these responsibilities should be divvied up have changed. Some responsibilities historically performed by the clinical operations unit as part of the trial manager’s responsibilities have shifted to the GCP QA. Meanwhile, the trial manager and clinical operations have retained some quality-related responsibilities, primarily QC-focused activities such as monitoring and corrective and preventive action (CAPA).

A 2014 article in “Applied Clinical Trials” entitled “The Evolving Role of the Clinical Quality Professional” summarized this evolution as follows:

“Historically, the Quality Assurance (QA) organization has been viewed as separate, independent auditing entity. Across the clinical development enterprise, the mindset is shifting from one of ‘quality as a rule’ to one of ‘quality as culture‘ where compliance is assured as part of the overall quality management and where quality and compliance is everyone’s responsibility.”

This aligns with the principles of a quality management system (QMS) and risk management, the key notions that underpin nearly all current regulatory policy,  explained David Fryrear, at that time Senior Director, GCP Operations and Pharmacovigilance Compliance, at Abbvie, said in that article.

“The clinical trial enterprise did not embrace these early on and, in many cases, it was a mix of befuddlement or dismissiveness that these truly only applied to manufacturing,” Fryrear said in the article. “After a few high-profile regulatory agency enforcement actions and rejections of products due to the quality questions, the industry started to take this seriously. …The QMS elements – CAPA, change management, etc. – are essential.”

Over the last couple of decades, as the clinical development side of the industry has caught up to this concept, the ever-evolving GCP QA unit has come to be responsible for the tasks previously delegated to the trail manager, such as:

• Review of the clinical trial protocol, risk management plan, oversight and monitoring plans, informed consent forms, and other essential documents referenced in regulations and key guidance;
• Ensuring that the informed consent form and trial protocol are designed to reduce user error;
• Creating and maintaining a unique risk management plan for each trial;
• Reviewing monitoring reports of site visits;
• Reporting key GCP quality and compliance metrics to clinical operations, clinical development and regulatory affairs staff;
• Escalating critical quality and compliance issues as appropriate; and
• Periodic review of the Trial Master File (TMF) throughout the clinical trial, including comparison against the clinical study report to verify that study reliability and data integrity requirements are met.

The GCP QA unit continues to have responsibility for the more traditional duties of auditing any CROs, laboratories, suppliers and clinical investigators, along with preparing sites for regulator inspections.

The trial manager’s quality duties focus more heavily on the routine monitoring and reporting tasks, including data source verification, and CAPA activities.

ICH Guideline is Critical

Effective implementation of a modern GCP QA plan must be grounded in a thorough understanding of applicable regulatory requirements and any associated guidance documents. Additionally, keeping up with current industry standards and best practices is necessary for companies that want to stay at the front of the new product development pack.

Since Congress in the mid-1970 directed the FDA to establish an agency-wide program of on-site inspections and data audits to monitor clinical trial execution and reporting, which resulted in the BIMO program to monitor sponsors, contract research organizations (CROs), institutional review boards (IRBs) and clinical investigators, the policies of the FDA and international regulators have continued to evolve based on precedents that arose from observations during BIMO and similar inspections.

Based on what these international regulators learned via their inspection programs, agencies from the US, EU and Japan developed the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (E6); Revision 1 was approved in June 1996 and Revision 2 in November 2016; the FDA made Revision 2 effective in March 2018. As a result, from the late 1990s through the present day, numerous FDA Form 483s issued after inspections of clinical trial sites have linked directly to lack of compliance with ICH E6. That means that medical product sponsors need to carefully consider the recommendations in that guideline in developing their GCP QA system.

A key feature of the ICH E6 guideline is the statement that sponsors may not delegate QA/QC system responsibility to a CRO or other entity. Use of a CRO can still trip companies up, however. Despite the fairly clear statement to the contrary, Form 483 observations still indicate that new drug or device sponsors often believe that they can largely delegate the responsibility for GCP QA to a CRO.

The initial ICH E6 guideline, however, is very clear that the sponsor of an investigational new drug or device must have its own QA/QC system in place for clinical trials, even if it outsourced key clinical trial operations to a CRO. According to that document:

“5.1 Quality Assurance and Quality Control

5.1.1 The Sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure Trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirements.

5.2 Contract Research Organization

5.2.1 A Sponsor may transfer any or all of the Sponsor’s Trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the Trial data always resides with the Sponsor.”

Revision 2 of the ICH E6 document aimed to further clarify regulator expectations of sponsors by adding an addendum to Section 5 of the guideline; that addendum requires that sponsors implement a system to manage quality end-to-end throughout the whole of a clinical trial and incorporates the concept of risk management as part of that system. The addendum states that:

“The Sponsor should implement a system to manage quality throughout all stages of the Trial process.

Sponsors should focus on Trial activities essential to ensuring human subject protection and the reliability of Trial results. Quality management includes the design of efficient Clinical Trial protocols and tools and procedures for data collection and processing, as well as the collection of information that is essential to decision making.

The methods used to assure and control the quality of the Trial should be proportionate to the risks inherent in the Trial and the importance of the information collected. The sponsor should ensure that all aspects of the Trial are operationally feasible and should avoid unnecessary complexity, procedures, and data collection. Protocols, case report forms, and other operational documents should be clear, concise, and consistent.

The quality management system should use a risk-based approach…”

The addendum further details that such a risk-based approach must include: critical process and data identification; risk identification, evaluation and control; and risk communication, review and reporting. All of these elements must be documented in a formal risk management plan, according to ICH E6 Revision 2.