By Steven Whittaker, The Avoca Group
On Nov. 18, 2019, the International Conference on Harmonization (ICH) Management Committee endorsed the Final Concept Paper ICH E6(R3): Guideline for Good Clinical Practice. The scope of revisions described within the paper includes a full rewrite and reorganization of ICH E6(R2) within an overarching principles and objectives document and two annexes. A draft of the overarching principles and objectives document and Annex 1, which is to focus on traditional interventional trials, is anticipated to be released within 18 to 24 months of the release of the concept paper. Annex 2, which will focus on nontraditional trial types such as pragmatic, decentralized, real-world evidence (RWE), and other trial designs, is anticipated to be released subsequently to the first two documents. Annex 2 will enable diverse approaches to a variety of clinical trial designs and innovative technologies.
During the 2020 Avoca Quality and Innovation Summit, held virtually in October, an interactive brainstorming system was used during a workshop on ICH E6(R3) to gather industry executives’ insights about guidance that would more rapidly and effectively enable quality adoption of innovative trial designs and technology. More than 325 clinical operations and quality unit executives from pharma, biotech, CROs, and other providers supporting clinical research actively participated in entering and upvoting their top-priority collaborative needs between industry, investigative sites, technology providers, regulators, and other stakeholders in order to influence regulatory guidance.
The following major topics and subtopics were addressed by the workshop attendees to determine the top prioritized (i.e., upvoted) opportunities for collaboration:
- Requirements for remote source data verification and source data review (SDV/SDR) – global privacy (e.g., GDPR)
- Pragmatic (RWE) trials
- Use of devices
- Digital endpoints
- Bayesian/Monte Carlo “virtual or decentralized” trial designs
- Machine learning – cofactor determination
eSource – Interoperability
With the increased global use of diverse electronic health records (EHR) systems by institutions conducting healthcare and clinical research, and the rapid adoption of technology and devices that generate eSource data, interoperability across systems and with electronic data capture (EDC) systems has become a major area of interest. The summit workshop executive participants prioritized the following needs and opportunities for guidance to more effectively enable interoperability of eSource systems and data.
- Guidance on connectivity of EHR and digital devices to EDC, especially in real-time context
- Guidance on remote access to electronic medical/health records (EMR/EHR), especially addressing secure interfaces, data security and the management of access within complex regions such as the European Union (EU)
- Data standardization, especially in the areas of remote platforms that enable user access management and integration of data including retention/destruction requirements. Concepts similar to the Clinical Data Interchange Standards Consortium (CDISC) were mentioned.
- Privacy requirements harmonized across global regions with clear electronic privacy authorization processes
- Minimum requirements for eSource system validation, including clarity on ownership for validation (e.g., technology system providers, investigative sites and networks, sponsors/CROs, ethics committees, or others). Guidance is needed on the required role for the sponsor/CRO when other organizations establish their unique eSource systems, including the requirements for computer system validations.
- Guidance on the use of mobile devices for data collection and processing
eSource – Requirements For Remote SDV/SDR) – Global Privacy (e.g., GDPR)
During the global COVID-19 pandemic, with the inability in numerous circumstances for study monitors to gain access to investigative sites for source data verification, efforts were rapidly pursued to determine options for remote SDV/SDR. Numerous challenges were experienced, especially with very diverse and often restrictive requirements around privacy and the ability to share source data using visual technologies, across regional boundaries or via temporary electronic storage and access locations. While in some instances regulatory agencies relaxed some requirements permitting remote SDV/SDR, these challenges prompted a very robust engagement from the summit workshop executives. The following needs were prioritized.
- Standardized privacy and data access guidance across regulators, including GDPR, and consistency of application across member states
- Clarity and consistency globally on acceptable data and source document sharing platforms, including the system requirements for such platforms. Established, clearly defined validation or verification responsibilities for sponsors when these systems are owned by investigative sites.
- Training requirements for individuals who will enter and access source information in the systems, especially clarity on expected minimum requirements and mandates
- Clarity on if/when ICH requirements supersede GDPR
- Requirements for patient consent for remote SDV/SDR
- ALCOAC requirements for remote SDV/SDR
- Guidance on redaction of documents for remote SDV/SDR
Pragmatic (RWE) Trials - Use of Devices
The use of devices, especially mobile devices, is experiencing rapid adoption within healthcare and clinical research. Regulators such as the PMDA, FDA, and EMA have expressed a desire to conduct horizon scanning1 to identify and prioritize innovative technologies and trial designs with the intent to generate global regulations for their use. It is anticipated that horizon scanning will be used during the preparation of ICH E6(R3) Annex 2. This topic within the workshop prompted the participating executives to contemplate desired clarifications and requirements appropriate for regulations. The following desires were prioritized.
- Requirements for managing technology updates (i.e., software or hardware updates during the course of a trial), including documentation requirements
- Guidance on wearable devices, including approaches to verify that the device is appropriately used only by the intended trial participant
- Privacy and GDPR requirements for wearable devices
- Acceptability requirements for use of personal devices (e.g., bring your own device (BYOD)) for electronic clinical outcome assessments (eCOAs)
- Requirements for data security controls
- Requirements for device verification, analytical validation, clinical validation, and source validation with responsibilities aligned to pharma/biotech, device providers and others. Can statistical approaches be incorporated to manage variability?
- Approved processes for deleting/destroying data after trial completion
Pragmatic (RWE) Trials: Digital Endpoints
Digital endpoints are fundamental components of primary, secondary, and safety endpoints within clinical trials. As such, the acquisition, processing, and reporting of digital endpoints, and regulations pertaining to these, will be vitally important during the interpretation of clinical trial results and thus will impact data interpretability for patient safety and for market authorization application review and approval processes. The workshop executives identified the following prioritized requirements to ensure alignment across sponsors and regulators.
- Clarity of audit requirements for data sources
- Verification and validation requirements across the complex sequence of steps to obtain clinically meaningful data, including the device collection of raw data, transformation of the raw data into clinical information, and the validation of clinical relevance for a disease state. What hardware and software validation requirements are necessary? What ownership and processes are required across the stakeholder groups?
- Requirements to ensure data integrity such as protection of blinded study information, management of data bias, and methods to “clean” data if the patient cannot be queried
- Clarity of digital endpoint evaluation criteria
- Global harmonization of inspection requirements for digital devices and endpoints
- Establishment of a library of generally accepted digital endpoints, including the potential for the use of novel digital endpoints (NDEs) to replace traditional clinical endpoints as regulatory accepted endpoints
Pragmatic (RWE) Trials: Bayesian/Monte Carlo “Virtual Or Decentralized” Trial Designs
Trial designs that include components of virtual or decentralized approaches, either entirely or in a hybrid fashion with traditional trial concepts, have become more popular within the industry to better enable access to patients in real-world settings, to enhance the inclusion of diverse patient populations, and to obtain real-world evidence from data collected by devices while patients are engaging in their normal life settings. COVID-19 has prompted the more rapid adoption of virtual or decentralized trials. Executives within the industry believe it is imperative that regulations adapt, while maintaining patient safety and data integrity. The following topics were prioritized during the executive workshop.
- Clarity on regulatory and legal acceptance and requirements for conducting telemedicine across country (e.g., EU) or state lines to enable effective patient support while maintaining appropriate privacy
- Establishment of harmonized global requirements for oversight of decentralized or virtual trials, including valid criteria and approaches for sponsor/CRO monitoring
- Guidance on requirements for principle investigator (PI) oversight of decentralized trials and permitted delegations to vendors or others
- Guidance for the reporting of serious adverse events (SAEs) from decentralized trials
- Validation requirements needed for use of Bayesian/machine learning, such as those built on Bayesian statistics
Pragmatic (RWE) Trials: Machine Learning – Cofactor Determination
The use of innovative technology and devices to collect clinical trial data, including digital endpoints, provides an opportunity to use large volumes of participant data for machine learning (ML) and the use of artificial intelligence (AI) for adaptive trial designs, patient support, and numerous other innovative trial concepts. Insufficient global regulatory guidance within this innovative space creates uncertainty for the ultimate use and interpretation of trials utilizing machine learning. Workshop executives identified the following prioritized desires for clarification on the use of ML and AI.
- Establishment of international, multilateral documentation standards and requirements for defining and using ML algorithms, including validation requirements and procedures
- Guidance on depth of ML algorithm validation and potential use of risk-based approaches
- Requirements for the maintenance of data lakes
- Data audit standards and requirements
- Training and documentation requirements for protocol designs with the use of AI and ML
The energy and engagement of these clinical operations and quality unit executives within the Avoca Quality and Innovation Summit Workshop on ICH E6(R3) demonstrates the passion and desire to align industry, regulatory, investigative site, and technology providers for the use of innovative technologies and trial designs for the benefit of clinical research and patient outcomes. Collaborative efforts should continue to pursue alignment across all stakeholder groups.
- Symposium for the draft ICH E8(R1) 25 July 2019, Yomiuri Holl, Tokyo, Japan
About The Author:
Steve Whittaker is a senior consultant with The Avoca Group. He is also a lead consultant for the pharmaceutical, biotech, and CRO industries providing expertise in project management, pharmaceutical development, clinical development, outsourcing strategies, and execution plans. Whittaker served as executive director of the Avoca Quality Consortium from 2011 to 2018, and for 14 consecutive years on the Advisory Board for the annual Partnerships in Clinical Trials program, chairing the board for two years. In 2009, Steve retired from Eli Lilly and Company, where he served as chief operating officer/sr. director of operations and project management for the cardiovascular/acute care platform.
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