Guest Column | January 27, 2025

FDA Provides Updated Draft Guidance To Support E6(R3)

By Jessica Cordes, senior consultant and trainer, Clinical Excellence GmbH

FDA-Approved-GettyImages-1186545957

In support of ICH E6(R3), which recently gained ICH approval but is not yet endorsed by regulators, the FDA has published draft guidance titled E6(R3) Good Clinical Practice: Annex 2, which emphasizes the importance of decentralized elements and the integration of real-world data. This article summarizes the key elements of the FDA's recommendations.

Informed Consent Process

The informed consent process must be tailored to the specific needs of the clinical trial, including the use of remote consent methods if applicable. Ensuring participants understand the consent information and verifying their identity is crucial. This can involve using multimedia tools to enhance comprehension and implementing secure methods for identity verification, such as digital signatures or video conferencing.

Investigator Oversight

Investigators must ensure that healthcare professionals performing clinical trial-related activities are appropriately trained and supervised. This includes delegating tasks to qualified individuals and providing necessary training on the protocol, investigator’s brochure, and other clinical trial-related documents. For clinical practices by healthcare professionals that do not require such knowledge, proper arrangements and oversight must ensure relevant information and records are available to the investigator.

The level of oversight should be proportionate to the risks to clinical trial participant safety and data reliability. This involves implementing risk-based oversight strategies that focus on critical aspects of the clinical trial and ensuring that all clinical trial-related activities are conducted in compliance with the protocol and regulatory requirements. Investigators should maintain appropriate documentation of oversight activities and ensure compliance with local regulatory requirements. This includes keeping detailed records of training, delegation, and monitoring activities.

Investigational Product Management

Sponsors should assess investigational product management approaches during protocol development.

Arrangements for shipping investigational products to participants must ensure privacy, proper receipt, and administration. This involves implementing secure shipping methods, tracking deliveries, and providing clear instructions for product use. To ensure proper delivery and administration of investigational products, sponsors may deploy systems like interactive response technology and digital health technologies (DHTs). Additionally, home nurse visits can be arranged to assist participants with product administration. Various methods for investigational product management may be used as appropriate. The product can be dispensed to the participant or a designated representative (e.g., caregiver, home nurse, local pharmacist) for administration at the participant’s location (e.g., home, local healthcare center). These processes must comply with regulatory requirements. Sponsors must implement processes to verify that the product is received by the intended recipient and that blinding is maintained if applicable.

Providing participants with support tools, such as online tutorials and contact details for technical support, can facilitate proper administration and compliance.

Engagement And Communication

Early engagement with stakeholders, including patients, healthcare professionals, and regulatory authorities, is crucial for the successful integration of real-world data (RWD) into clinical trials. This involves addressing issues related to infrastructure, routine workflow integration, and training needs.

Engaging Patients And Advocacy Groups

Involving patients, advocacy groups, and communities helps ensure that the design is patient-centric and that the DHTs used are suitable for the target population. Early involvement also helps identify areas where additional training or support may be needed, enhancing participant compliance and clinical trial success.

Assessing the suitability of DHTs for the patient population is critical. This includes evaluating the ease of use, accessibility, and potential barriers to adoption. Providing clear instructions and support can help participants effectively use these technologies, ensuring accurate data collection and adherence to the protocol.

Engaging Healthcare Professionals And Investigators

Early engagement with healthcare professionals and investigators is vital to address infrastructure needs and integrate routine workflows with the protocol. This includes ensuring that the necessary equipment, technology, and support systems are in place to facilitate the smooth conduct of the clinical trial.

Collaborating with healthcare professionals and investigators during protocol development helps ensure that the design is practical and feasible. This collaboration can identify potential challenges and develop strategies to address them, enhancing the clinical trial’s overall efficiency and effectiveness.

Integrating Real-World Data

The integration of RWD into clinical trials is transforming the landscape of clinical research. By leveraging data from electronic health records (EHRs), claims data, and registries, researchers can enhance the relevance and applicability of their findings.

Each source offers unique insights but also presents challenges in terms of data standardization and integration. EHRs provide detailed clinical information, claims data offer insights into healthcare utilization and costs, and registries can provide longitudinal data on specific patient populations. The diversity of these sources can enrich clinical trials but requires careful consideration of how to harmonize and integrate the data effectively.

The control over data collection varies depending on whether the data are primary or secondary. Primary data collection involves gathering new data specifically for the clinical trial, while secondary data collection involves using existing data. Sponsors must ensure that the data elements collected are relevant and reliable for the clinical trial’s objectives. This includes establishing clear protocols for data collection, ensuring data quality, and addressing any potential biases that may arise from using secondary data.

Data from different sources may use varying terminologies and standards, leading to potential inconsistencies. Standardizing data formats is crucial for ensuring comparability and reliability. This can involve mapping different terminologies to a common standard, using standardized data models, and employing data harmonization techniques. Ensuring that data from different sources can be accurately compared and integrated is essential for the validity of the clinical trial results.

Participants may move between healthcare systems or experience events that are not captured in the data. Thus, addressing these gaps through robust data management strategies is essential. Ensuring the quality of data collected in clinical practice or registries involves maintaining consistent vocabularies and coding systems. De-identification methods must be employed to protect participant privacy. This includes using standardized coding systems and implementing robust data governance practices to ensure data integrity. De-identification techniques, such as pseudonymization, are critical for protecting participant privacy while allowing for meaningful data analysis.

Sponsors should establish agreements with data owners to allow regulatory authorities access to source records and data for inspections. These agreements should outline the terms of data access, including the scope of data sharing, data security measures, and the responsibilities of each party.

Linking data from multiple sources involves combining data from different sources to create a more comprehensive data set.  However, it requires careful consideration of data privacy and security, as well as robust methods for accurately matching records across sources.

Addressing data security vulnerabilities, including cybersecurity and data privacy, is paramount, especially when using DHTs like wearables. This involves implementing strong encryption methods, secure data transmission protocols, and robust access controls, as well as regular security assessments and audits conducted by sponsors.

Integrating RWD into clinical trials offers significant opportunities to enhance the relevance and applicability of research findings. By addressing the challenges related to data sources, variability, quality, ownership, and security, researchers can ensure that their trials are robust, reliable, and compliant with regulatory standards.

Where Annex 2 Guidance Succeeds And Falls Short

The FDA's updated draft guidance on ICH E6(R3) Annex 2 provides a solid framework for integrating decentralized elements and RWD into clinical trials. It excels in emphasizing the importance of tailored informed consent processes, which facilitate broader participation while ensuring regulatory compliance. The guidance also highlights the need for risk-based investigator oversight and comprehensive investigational product management, ensuring proper delivery and administration.

However, the guidance falls short in addressing data standardization and integration challenges. It mentions these issues but lacks concrete strategies for harmonizing different data formats and terminologies. Additionally, while it touches on data privacy and security, it does not provide specific recommendations for addressing cybersecurity vulnerabilities, especially with the increasing use of DHTs like wearables.

Remaining questions include how to handle data gaps when participants move between healthcare systems and how to ensure data quality from various sources. More practical examples and case studies would also enhance the guidance's applicability in real-world scenarios.

Overall, while the guidance is a significant step forward, addressing these critical aspects would enhance its effectiveness and applicability in clinical research.

About The Expert:

Jessica Cordes started her clinical operations career in 2009, working at various companies including Big Pharma and several small to midsize biotech companies. She gained extensive experience on different levels from country study management to global study management and, since 2018, leadership in clinical operations. During her time at Medigene and Immatics, she structured the clinical operations department, built cohesive global teams, and implemented GCP and ATMP-compliant processes. For more than 12 years, she has been working in oncology clinical trials (including hemato-oncology as well as solid tumors) and with ATMPs since 2018. Since 2023, she has been working as an independent consultant and trainer, supporting small companies in building their clinical operations group and setting up their clinical trials for success. She provides a GCP refresher course, covering ICH E6(R3) with Annex 1 and 2, via her Clinical Excellence Training Academy.