Evolving Standards: Good Clinical Practice Insights from US FDA, MHRA UK, and Health Canada

Abstract

As clinical trial design and conduct continue to evolve with innovative approaches, new technologies, and emerging data sources, regulatory frameworks are undergoing significant updates to align with these advancements. This article explores recent revisions to the International Council for Harmonization (ICH) Guideline for Good Clinical Practice (GCP) E6(R3) and the regulatory perspectives on adopting a risk-proportionate approach to trial design and conduct. Drawing from insights shared at the FDA-MHRA-HC 2024 Joint GCP Symposium, this article highlights the key themes shaping the future of clinical trials, including quality-by-design (QbD), risk proportionality, and cross-regulatory collaboration. Additionally, this article addresses the impact of the COVID-19 pandemic in accelerating trial innovations, such as the use of decentralized trial elements and digital health technologies (DHTs), while also emphasizing the need for regulatory flexibility to accelerate their adoption. Regulatory agencies, such as the US-FDA, MHRA-UK, and Health Canada, have issued guidance to promote clinical trial flexibilities and proportionate, risk-based approaches, ensuring the protection of participant rights, safety, and well-being and overall reliability of trial results. These updates advocate for proportionate approaches to trial oversight, which allow for innovation while safeguarding the trial’s critical to quality factors. As regulators continue to refine their practices and enhance collaboration, the integration of QbD and risk proportionality into clinical trials and cross-regulatory collaboration will ultimately drive more efficient, participant-centered trials and improve the global clinical research landscape.

As clinical trial design and conduct continue to evolve with the integration of innovative and adaptive approaches, new technologies, and novel data sources, recent updates to regulatory frameworks and revised guidelines are reshaping the way studies are planned and conducted.¹ This article is a summary of the FDA-MHRA-HC Joint Good Clinical Practice (GCP) Symposium held in February 2024² and focuses on the insights presented and discussed at the event. It examines recent regulatory updates and emerging trends in clinical trial conduct, highlighting key revisions to the International Council for Harmonization (ICH) guideline for GCP E6(R3). It explores regulatory perspectives on the risk proportionate approach to trial design and conduct outlined in ICH E6(R3)^3,4 and highlights the collaborative efforts of the US Food and Drug Administration (US-FDA), Medicines and Healthcare products Regulatory Agency U.K. (MHRA-UK), and Health Canada (HC). Drawing on these insights from the FDA-MHRA-HC 2024 Joint GCP Symposium,² this article discusses ICH E6(R3)’s foundational principles of quality-by-design (QbD) and risk proportionality, and also examines the role of cross-regulatory collaboration, all of which are key drivers guiding the evolution of clinical trial design, conduct, and regulatory oversight. Although some time has passed since the symposium, the discussion remains highly relevant, as implementation of ICH E6(R3) continues globally and the clinical trial community is actively navigating its practical application. Understanding these concepts will help the interested parties better navigate the complexities of the current clinical trial landscape, including its regulatory frameworks.

The COVID-19 pandemic served as a catalyst for change in the clinical trial enterprise, accelerating the adoption of innovative methodologies and technologies, such as decentralized trial activities, remote and centralized monitoring, and digital health technologies (DHTs).⁵ These adaptations demonstrated the potential for conducting clinical trials in ways that facilitate broader patient engagement, greater flexibility in trial conduct, and more efficient data collection.^6–11 While industry and regulators have made significant strides in embracing these novel trial designs, operational approaches, and data sources, the pace of change has not been consistent across the clinical trial enterprise. Some have embraced QbD, risk proportionality, and innovation, while others have faced challenges due to traditional mindsets, lack of resources, or concerns about regulatory acceptability.^12,13

Regulatory frameworks have also been evolving to reflect these changes, promoting greater harmonization and collaboration between regulators. To support clinical trial innovation within the bounds of regulatory requirements, FDA, MHRA, and HC have issued numerous guidances aimed at fostering QbD, risk proportionality and new trial methodologies, including on topics such as DHTs, decentralized and pragmatic trial elements, risk-based monitoring, remote inspections, and the use of real-world data.^14–32 These guidances promote a flexible and proportionate approach to trial design and conduct, enabling innovation while safeguarding participant protections and ensuring data reliability. This shift encourages sponsors to adopt trial strategies that prioritize participant needs, protect their rights, safety, and well-being, and uphold the integrity and quality of data throughout the clinical trial lifecycle.

Additionally, at the onset of the COVID-19 pandemic, regulators introduced remote assessment and inspection of clinical trials, utilizing emerging technologies to maintain oversight while ensuring the continuity of trials.^{14,17,33–42} This shift to remote assessments and inspections not only has allowed regulatory agencies to adapt during the pandemic but also it has led to the continued evolution of inspection practices, including remote and hybrid inspections that allow for greater flexibility in oversight. While collaboration between regulators was already in motion before the pandemic, the urgent need for innovation and adaptability accelerated during this period, fostering deeper cooperation across agencies.⁴³ This shift toward greater collaboration and flexibility has laid the groundwork for ongoing progress in clinical trial conduct, as reflected in the discussions from the recent Joint GCP Symposium.²

QUALITY-BY-DESIGN AND RISK PROPORTIONALITY

The multifaceted and complex nature of clinical trials, encompassing diverse patient populations, novel operational approaches, and advanced technologies, necessitates a comprehensive understanding of the interplay between various global regulatory frameworks. In this context, the ICH E6 revisions are designed to address these complexities and aim to maintain participant protections and clinical trial quality throughout the clinical trial lifecycle. The updates to ICH E6 offer recommendations applicable to a broad range of trial designs, supporting modernization and innovation in trial design and conduct, while also fostering greater harmonization across regulatory authorities, including both ICH member countries and those that adopt ICH guidelines. Central to these changes are the key principles of QbD and risk proportionality which ensure fit-for-purpose clinical trial quality; participant rights, safety, and well-being; and the reliability of the trial results.^3,4,44

ICH E6(R3) should be read in conjunction with other ICH efficacy guidelines, including ICH E8(R1), which outlines general considerations for clinical studies.⁴⁴ ICH E8(R1) and ICH E6(R3) define clinical trial quality as fitness for purpose.^3,44 Clinical trial quality is considered fit-for-purpose when the data are of sufficient quality to meet the trial’s objectives, provide confidence in the trial’s results, support good decision making, and adhere to regulatory requirements.³ Achieving this level of trial quality involves applying the principles of QbD and risk proportionality throughout trial design and conduct.

QbD is an approach that emphasizes embedding quality into the trial from the outset, prioritizing quality at every stage of the trial to ensure that the trial is designed and conducted to meet its objectives and generate reliable results. By focusing on what is essential to answer the research question, QbD enables sponsors to streamline processes by eliminating unnecessary tests, procedures, and data collection that do not contribute to answering the research question. This helps reduce unnecessary protocol complexity and minimizes the burden on participants, clinical investigators, trial sites, service providers, and sponsors. The result is a more efficient, focused, and simplified trial with potentially fewer data quality issues. QbD also facilitates timely identification and management of risks throughout the trial lifecycle, helping to prevent or mitigate errors that could affect key trial-related decisions (such as dose escalation) and the reliability of trial results.³ Notably, QbD supports patient-centered strategies by incorporating patient feedback in trial design, for example by using such feedback to design electronic patient-reported outcomes to ensure they are fit for purpose. This not only makes data collection more efficient and relevant but also reduces participant burden. Additionally, QbD fosters cross-functional collaboration among all parties involved in trial conduct to identify factors critical to the trial’s quality and inform risk assessments and the implementation of appropriate and proportionate strategies to safeguard participant rights, safety, and well-being and the reliability of trial results.^3,4,44,45

Risk proportionality, a core element of QbD and a key principle of ICH E6(R3), should be applied to all types of trials and within various domains of clinical trial design and conduct. It ensures that oversight and the level of resources applied to managing risks to clinical trial quality are commensurate with the potential of those risks to affect the protection of participants and the reliability of trial results (e.g., greater risks to the trial results would require more stringent controls and oversight). By applying this approach to trial management (i.e., risk-based quality management or RBQM), tailored strategies can be implemented to address the unique challenges and complexities of each trial, enhancing the overall effectiveness and efficiency of the trial process.

The revisions to ICH E6(R3) also underscore the importance of applying risk-proportionality to oversight by sponsors and investigators, ensuring oversight aligns with the importance of the data being collected and the risks to participant protections and the reliability of results. Effective risk-proportionate oversight necessitates that all involved in trial conduct have a clear understanding of the critical to quality factors and risks to those factors. That understanding should be used to tailor oversight to the specific critical to quality factors of each individual trial instead of taking a one-size-fits-all approach. As discussed at the Joint GCP Symposium, risk-proportionate sponsor and investigator oversight is tailored to account for the protocol’s unique objectives, endpoints, and trial processes and procedures. Risk-proportionate oversight also takes into consideration the trial’s complexities and challenges, as well as the experience of sponsors, investigators, and service providers involved in the trial conduct. These considerations should guide the approach to oversight throughout the trial including in key trial-related plans, such as service provider management, communication strategies, monitoring, data governance, and safety monitoring.

In terms of data governance, applying risk-proportionality helps prioritize critical data, systems, and processes, ensuring they are implemented and managed to maintain data reliability throughout the data lifecycle. Effective data governance based on risk proportionality ensures, for example, that critical computerized systems used in trial conduct are fit-for-purpose and used appropriately.³ Validation of systems, such as interactive response technology systems used for dose allocation and dose adjustments, is essential to ensure that dose calculations are accurate and participants receive the correct dose. Significant issues have been identified in inspections when such systems were not properly validated. Focusing on critical computerized systems and designing them to collect the data required by the protocol not only enhances data accuracy, but also mitigates risks associated with data collection and processing errors.

Effective risk-proportionate data governance should also support the trial’s critical processes, such as randomization, dose escalation, and blinding, as well as the key decision-making processes throughout the trial conduct. Safeguarding these critical clinical trial processes is crucial for maintaining the trial’s integrity.³ This includes managing unblinding procedures, establishing clear protocols for data finalization prior to analysis, and appropriately allocating data to analysis sets. Additionally, risk-proportionate data governance frameworks should be adaptable to allow for systematic changes, when necessary, in response to feedback from ongoing monitoring and evaluation of critical data, processes, and systems. Changes to the protocol and trial design should be aligned with corresponding modifications to systems and processes that are critical to quality, and these changes should be documented, justified, and compliant with regulatory requirements.^46,47

The following case examples illustrate how the application of QbD and risk proportionality in the design and conduct of a trial could have helped to mitigate the negative impact on data quality. One case presented during the Joint GCP Symposium highlighted a pivotal rare disease trial where a cascade of issues stemmed from errors in the design of the electronic case report form (eCRF) used to collect the primary efficacy endpoint. The design error led to significant data inaccuracies in critical data. These issues were further complicated by the contract research organization’s (CRO) access to edit the eCRF. After the trial was unblinded, the sponsor and CRO implemented remediation actions, but the remedial actions taken raised further significant concerns about the reliability of the trial data. Furthermore, when the error was identified, the sponsor failed to assess the risk and impact of the issue, as well as any remedial actions on the reliability of the data. Had a QbD approach been applied, with a stronger focus on primary efficacy endpoint data collection throughout trial design and conduct, through thorough eCRF validation, data capture processes, monitoring, and blinded dry runs, these issues could have been mitigated.

Another case example involved an inspection of a CRO that led to the identification of a breach of participant confidentiality. Partially identifiable data were stored in an electronic data capture system and the system’s audit trails. The informed consent provided by participants allowed pseudonymized data to be transferred and stored only within the United Kingdom⁴⁸; however, the data were held on servers located outside of the United Kingdom. The inspection revealed several root causes, including an inadequate risk assessment and procedure that failed to identify the full extent of personally identifiable data captured.

As the clinical trial landscape continues to evolve, applying the principles of QbD and risk proportionality is essential to robust trial design and conduct. Regulatory agencies have long advocated for a risk-proportionate, quality-focused approach that prioritizes participant protections, data reliability, and operational efficiency. The recent updates to the ICH E6(R3) guideline now explicitly integrate QbD and risk proportionality principles. By harmonizing these expectations globally, these updates aim to facilitate more consistent and practical implementation by sponsors across different regions. Regulatory agencies are reinforcing the importance of these principles through changes to their regulations and regulatory frameworks. For example, the UK’s forthcoming clinical trials regulations will include provisions for risk proportionality, with the legislation being signed into law and coming into effect on 28 April 2026.^26,32,49 This regulatory development is part of broader efforts to modernize trial oversight and ensure that risk-based approaches are embedded in clinical trial practices.

Beyond regulations and written guidance, regulatory agencies are using workshops, pilot projects, and public–private partnerships (PPPs) to test and refine tools in real-world settings, with the intent of developing case studies and examples that can inform broader adoption. For example, this joint symposium, which forms the basis of this summary, is one such example. Additionally, in the United States, the FDA works through PPPs such as the Clinical Trials Transformation Initiative (CTTI) to develop evidence-based recommendations, practical toolkits, and case studies that help operationalize QbD and risk-proportionate approaches across diverse trial contexts. These resources (e.g., frameworks, toolkits, and implementation examples) can be widely used by sponsors, investigators, and academic partners to translate principles into practice.⁵⁰

Within FDA, CDER’s Center for Clinical Trial Innovation (C3TI) further advances implementation by serving as a hub for modern trial methods. C3TI coordinates innovation across CDER, facilitates knowledge-sharing through public workshops and forums, and operates a Demonstration Program that enables early engagement with sponsors to pilot and scale new trial approaches. Current demonstration projects include Bayesian statistical methods, selective safety data collection, and pragmatic trials embedded in routine practice, all designed to generate regulatory learning and publicly shareable examples of implementation.⁵¹ Collectively, these initiatives indicate a stepwise shift from principle-setting toward operational clarity, with regulators and the clinical trial community jointly building the case studies and tools needed for consistent adoption.

To effectively implement QbD and risk proportionality, a paradigm shift is essential. This shift requires those designing trials to tailor the trial design and processes to the unique objectives and risks to the critical to quality factors of each trial. Additionally, a multidisciplinary and cross-functional collaboration should be incorporated from the outset, during trial design and planning, to integrate diverse expertise and relevant perspectives. While the regulatory support for QbD and risk proportionality is clear, there remains a need for practical guidance on how to effectively apply these principles. Some foundational principles are outlined in ICH E6(R3) and national regulations, but further clarity on effective implementation strategies, risk assessment tools, and real-world examples from sponsors and regulators would help ensure that these principles are applied consistently and with maximal benefit. Regulators encourage ongoing dialogue, knowledge sharing, and the development of resources to assist sponsors in successfully integrating risk-proportionate and quality-driven strategies into their clinical trials.

COLLABORATION

As clinical trials increasingly span multiple countries and industry seeks drug approvals across regions, collaboration among regulatory agencies has become essential. These collaborative efforts aim to foster a more efficient and unified approach to trial oversight, streamlining processes, reducing redundancies, and strengthening regulators’ ability to protect participants, ensure data reliability, and maintain public confidence in the regulatory system. Regulators are leveraging information-sharing agreements and international collaborations such as Pharmaceutical Inspection Cooperation Scheme (PIC/S)^52,53 to establish common standards, harmonize inspection practices, and exchange critical information, including details on inspections. The PIC/S Expert Circle for GCP, founded in 2022, provides a collaborative framework to drive a more consistent inspectional focus on CTQ factors. For instance, global inspectorate training and joint inspections conducted under PIC/S are helping to align how inspectors evaluate CTQ factors such as endpoint data collection, informed consent processes, and system validation. While complete harmonization will require sustained effort, the trajectory is clear: regulators are increasingly converging on a shared understanding of what constitutes trial quality and how it should be assessed in practice. This is expected to foster greater predictability for sponsors and to ensure that participant protections and data reliability are safeguarded consistently across jurisdictions.^52,53

The benefits of collaboration among regulatory agencies are numerous. One of the primary advantages is the opportunity to learn from each other. By sharing knowledge and best practices, agencies can also improve their regulatory processes and enhance their oversight capabilities. Regulatory agencies can exchange inspection information, intelligence, and compliance trends, which enhance their ability to monitor and assess risks associated with clinical trials. This exchange of information contributes to the overall integrity of the regulatory system and helps ensure that all parties are informed of potential issues in real-time. Collaboration also allows for the efficient use of resources. By sharing information and conducting joint inspections, agencies can reduce duplication of efforts, which is especially important in a landscape where resources may be limited. This cooperative approach not only saves time and money but also enables regulators to focus their efforts on the most pressing issues, such as safety concerns or compliance violations.

Harmonization of regulatory expectations offers several significant advantages. Through collaborative efforts, agencies can work towards aligning their requirements and practices, reducing the regulatory burden on sponsors conducting multi-national trials. A more harmonized regulatory environment not only streamlines the trial process but also promotes innovation, enabling quicker access to therapies for patients across different regions.

The role of collaboration among regulatory agencies in the future is paramount, especially as the clinical trial landscape continues to evolve. Regulatory agencies continue to adapt their approaches to keep pace with new trial designs, methodologies, and technologies. An important aspect of this adaptation will be ensuring that inspectors are adequately trained to assess risk proportionate and novel operational approaches and that training experiences are shared across agencies. Additionally, efforts are underway to align communication messaging among interested parties through outreach initiatives, such as symposia, conferences, articles, and updated guidance documents. Through these collaborative efforts, regulatory agencies can continue to promote GCP compliance among sponsors and aim to drive upstream compliance, share best practices, and foster a culture of accountability and transparency that encourages adherence to regulatory standards.

Building on this foundation of collaboration, consistent implementation of ICH E6(R3)’s foundational principles across global clinical trials requires attention to diverse regulatory, cultural, and operational contexts. Achieving consistency depends on an adaptable quality management system that upholds participant protection and ensures reliable trial results while accommodating regional differences. Future efforts should focus on strengthening global capacity and collaboration through targeted actions that make the application of ICH E6(R3)’s risk-based framework consistent and sustainable in practice. This includes developing training programs to promote a common understanding of QbD, CTQ factors, and risk proportionality among sponsors, investigators, service providers, and regulators; supporting infrastructure that enables reliable data collection, oversight, and quality management; advancing regulatory harmonization to reduce duplication and promote alignment in quality expectations; and fostering shared learning through international partnerships, joint assessments, and open exchange of implementation experiences. Collectively, these operational efforts can enhance the global capability to apply ICH E6(R3)’s risk-based framework effectively across diverse trial settings.

CONCLUSION

The evolution of clinical trials necessitates a comprehensive approach to trial design and conduct that incorporates QbD, risk proportionality, and collaboration. With the recent updates to the ICH E6(R3) guideline, sponsors and clinical investigators have opportunities to navigate the complexities of trial design and conduct more effectively while ensuring participant safety and data reliability remain core priorities. As new technologies and methodologies are integrated into trial processes, it is critical to maintain a focus on these core priorities.

The integration of QbD, risk proportionality, and collaborative efforts among regulatory bodies will pave the way for a new era of clinical trials. Regulators have long advocated for and supported the adoption of QbD and risk proportionality and actively encourage sponsors to embrace these principles. With these principles now embedded in ICH E6(R3), the momentum for change is stronger than ever. By embracing these principles, sponsors, clinical investigators, and regulators can better anticipate and adapt to future demands, creating a clinical trial ecosystem that better serves patients and is more responsive, responsible, and impactful. Moving forward, clear guidance on effectively implementing these principles will be essential.

Ultimately, the goal is to ensure that clinical trials are conducted in a way that safeguards participant safety and produces reliable trial results, benefiting both patients and public health. As collaboration deepens and expands, regulatory authorities will be better positioned to navigate future challenges, paving the way for a more harmonized and efficient regulatory landscape that meets the needs of a global population. This collective effort will facilitate the faster development of safe and effective therapies, reduce the burden on trial participants, and preserve public trust in the clinical research enterprise.