FDA, MHRA, Health Canada Joint GCP Symposium Focuses On 3 Key Topics

By Enith Morillo, Cadoret Global

The U.S. FDA, the U.K. Medicines & Healthcare products Regulatory Agency (MHRA), and Health Canada (HC) recently came together for a three-day symposium on good clinical practices (GCP). The primary focus areas of the symposium were the ICH E6 harmonized guideline, remote regulatory assessments, and good pharmacovigilance practices. This article shares the key highlights and takeaways.

Focus Area 1: ICH E6 Harmonized Guideline

With the rapidly changing clinical trials landscape and the need to modernize, harmonize, and adapt, a large focus of the symposium was on the proposed changes to the ICH’s E6 harmonized guideline. Regulators across the three agencies were able to provide valuable insight into the changes and the rationale behind these.

A noteworthy change in the E6 guideline is the paradigm shift on risk. Whereas in the past risk management was a “nice to have”, the expectation from regulatory agencies moving forward is that risk management is adopted and implemented in all aspects of the trial. Sponsors are now expected to embrace risk management in a clinical trial’s design and conduct, incorporating an ongoing review of risk as the trial progresses. The expectation is that risk is assessed continuously throughout the life cycle of the trial to account for amendments to the protocol, changes to the trial, service providers, and supporting processes, among others.

In addition, sponsors’ responsibilities will include building quality into the design of the clinical trial by being able to identify factors that are critical to the integrity of the trial and managing risks to those factors. Regulators’ expectations are that sponsors take a proportionate and risk-based approach to quality management to ensure priority and adequate focus and resources are placed where they matter most. One of the sessions highlighted the importance of sponsors having leadership that promotes an open reporting culture, encourages investigation, and supports proportionate management of any critical errors.¹

Sponsors’ oversight of trial-related activities that are transferred to service providers is also emphasized in the guideline and continues to be of utmost importance, especially in the context of the bioresearch monitoring (BIMO) clinical investigators’ FDA 483 observation trends and recent warning letters.

The revised guideline highlights the gravity of protecting not only the safety but, as importantly, the confidentiality of trial participants. Consequently, significant changes are proposed around data governance. With an entire new section on the data life cycle and computerized systems, regulators expect sponsors to also apply a risk proportionate approach to data governance by:

• identifying what data, computerized systems, and data governance processes are critical to data integrity and clinical trial quality,
• focusing resources on critical data, systems, and processes to ensure the reliability of the data,
• understanding what is critical to quality, and
• reviewing and evaluating risk throughout the life of the trial, not only at its initiation, by updating and documenting risk assessments and mitigations.

Another change worth noting in the revised guideline is the shift from essential documents to essential records. With updated definitions and more detail on record management to accommodate new technologies and complexities, the guideline provides more guidance on what makes a record essential. Further, it includes clearer responsibilities of both clinical investigators and sponsors when it comes to essential records’ type and quality, sharing, use, and storage.

Table 1: Similarities & Differences Between RRAs and Inspections²

Focus Area 2: Remote Regulatory Assessments

Aside from time well spent on the revised ICH E6 guideline, the symposium included valuable sessions on remote regulatory assessments (RRAs). Starting with a recap on how inspections were impacted by the COVID-19 pandemic and how the U.S. FDA has developed a more robust process for RRAs, a point that was driven home is that they continue to be a tool for remote examination of FDA-regulated establishments and/or their records to evaluate compliance with applicable requirements but do not substitute for or equate to a regulatory inspection.In the context of marketing applications, U.S. GCP inspections generally include clinical investigators (CI), sponsor-investigator, sponsors, and contract research organizations (CROs).

A lesson learned from the pandemic is that RRAs can be useful in the assessment of data reliability, subject safety, and clinical trial conduct. However, the limitation of RRAs is in what they can cover, with inspections being comprehensive 97% of the time, as compared to RRAs at 5%. Coincidentally, the symposium coincided with the release of the FDA’s draft guidance for industry on Conducting Remote Regulatory Assessments: Questions and Answers.

Both MHRA and Health Canada regulators also touched on how their agencies pivoted to remote compliance assessments during the pandemic and presented on their respective initiatives and resources on GCP compliance. Health Canada shared the scope and activities that fall under their clinical trial compliance program, their guide on risk classification for observations related to clinical trial inspections, and their searchable drug and health products inspections database (DHPID). Similarly, MHRA touched on the regulations that grant it the right to inspect any site involved in clinical trial activities in the UK, their national program covering both systems and study-specific inspections (risk-based and triggered), as well as their voluntary Phase 1 accreditation scheme.

RRAs were also discussed in the context of the postmarketing adverse drug experience (PADE) compliance program and risk evaluation and mitigation strategies (REMS) compliance program, as an alternate compliance tool being piloted since 2023.

Focus Area 3: Good Pharmacovigilance Practices

The symposium concluded with important sessions on good pharmacovigilance practices (GPV) and covered the progress being made by the PIC/S expert circle to develop expertise by knowledge sharing, dissemination, and review of GPV related policies and documents to ensure harmonization of inspection procedures and techniques. Sessions included the use of artificial intelligence in pharmacovigilance and general regulatory updates from each of the participating agencies.

One of the sessions touched on the continued efforts of the U.S. FDA, MHRA, and Health Canada to conduct joint inspections, and how the pandemic only strengthened the need for collaboration. As an example, Health Canada conducted its first joint GPV inspection with the European Medicines Agency in 2021. The virtual inspection lasted 10 days, with daily briefings between inspectors, shared IT tools, and dedicated sessions on specific requirements for each regulatory agency.

Overall, the symposium provided valuable insight on how regulatory agencies are striving for transparency in their efforts to modernize, harmonize, and adapt to continue to foster compliance without hindering innovation.

References

1. ICH E6(R3) Draft – Good Data Governance Practices, Cheryl Grandinetti, Pharm.D., Shila Rastegar, MSc, and Andrew Fishe. February 2024.
2. Remote Regulatory Assessment (RRA) for Marketing Application Review. Jenn Sellers, M.D., Ph.D., FAAP. February 2024.

About The Author:

Enith Morillo, M.Sc., is the founder, president, and principal consultant of Cadoret Global, a quality and compliance consulting firm that specializes in supporting virtual, early-stage, and small pharmaceuticals in taking their investigational drug through development and into Phase 1-2 clinical trials. Cadoret Global is a woman-owned and minority-owned certified company and an alumni of the Goldman Sachs 10,000 small businesses program. She can be reached at Enith.Morillo@CadoretGlobal.com or on LinkedIn.