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As 2024 draws to a close, the Regulatory Considerations Data Management Expert Group (DMEG) has been actively reviewing two key FDA guidance documents:

– Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers.
– Guidance on Conducting Clinical Trials with Decentralized Elements.

Insights from these reviews are expected to be shared in 2025, marking the start of a year packed with regulatory milestones and challenges.

Among the priorities for 2025 is a detailed evaluation of the ICH E6(R3) Annex 2, currently open for public review until March. This annexe addresses the complexities of Good Clinical Practice (GCP) in the context of diverse trial designs, decentralised elements, and real-world data sources. DMEG plans to submit comments on behalf of ACDM and provide practical considerations for the data management community once finalised.

In addition, DMEG will assess the implications of the upcoming ICH E6(R3) General Principles and Annex 1 guidelines, which are anticipated to take effect shortly. These updates are expected to redefine requirements and introduce new challenges for clinical data management. The group will focus on helping the community integrate these changes smoothly into business-as-usual activities, ensuring compliance while maintaining efficiency.

Stay tuned for updates as DMEG continues to provide guidance and leadership in navigating the evolving regulatory landscape.

This year our focus has switched away from generalised RBQM to applying risk-based approaches to delivering Data Management. This is a huge topic and one that has stimulated much conversation over the course of our recent meetings. The DMEG has invested much discussion into the fundamentals of Risk-Based Data Management as well as discussions on how to pivot operational practices accordingly. We have been lucky to hear practical insights from some the DMEG members in these areas from projects that have or are running in their organisations.

Given the wealth of information and discussion that has taken place in the DMEG this year, our aim is now to distill our discussion and learnings into a paper that we can share with the wider ACDM membership. We look forward to being able to share more insights on this topic in due course.

– Rich Davies, Risk Based Quality Management (RBQM) DMEG Chair

Find out more about the RBQM DMEG here.

The Audit Trail Review (ATR) DMEG has been hard at work putting the finishing touches on a paper around ATR, titled Getting started with Audit Trail Review in Clinical Trial data: An Essential Guide.

This guide draws on our combined understanding and knowledge of this complex process. The goal of the paper is to demystify the implementation of an ATR process for clinical trial data, outlining the essential aspects, with suggestions and recommendations for how organisations can get started with this process. We share examples of findings and operational insights into the process, discuss CRO and Vendor perspectives, and conclude with thoughts on future directions in the ATR space.

We are pleased to share that the paper can now be read on our ATR DMEG page. Click here to find out more about our work and view the paper.

– Jennifer Nielsen, ATR DMEG Chair

The Regulatory Considerations DMEG are waiting for the release of ICH GCP E6 (R3) Annex 1 effective (expected by end of the year) and Annex 2 draft for review by end of September. Once released, we expect to review Annex 2 on behalf of ACDM and send comments to the authors.

In June, I attended as a representative of the ACDM at a GCP Inspectors Working Group, where there were representatives from the Danish regulatory authorities, the eClinical Forum Essential Metadata team, and the industry. The scope of the meeting was to gather feedback on the ongoing work on essential metadata conducted by the eClinical Forum. It was a two-day meeting, with the first day focused on essential metadata and the second day on new potential guidance regarding AI.

The authorities have received many questions asking about what is or is not essential metadata, the stance taken in ICH E6 (R3) is that it is the sponsor’s responsibility to define the essential metadata for their trial, and to ensure that all essential metadata remains available for inspection (in the TMF, in the original system, or in some other fashion) for the full retention period. The inspectors will then comment on the available essential metadata when performing inspections. It was decided that there should be a formal presentation of the list produced by the eClinical Forum to the full EMA GCP IWG when it is released, and that this is preliminarily planned for Q1 of 2025.

With regards to the AI session, the industry stakeholders at the meeting agreed that the draft AI guidance document written by the DKMA was a good guidance, and they would like to see it released as an EMA guidance.

– Silvia Perez Torres, Regulatory Considerations DMEG Chair

Find out more about the Regulatory Considerations DMEG here.

The Conducting Clinical Trials With Decentralized Elements final guidance has now been released, and provides recommendations for sponsors, investigators, and other interested parties regarding the implementation of decentralized elements in clinical trials.

Read here: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/conducting-clinical-trials-decentralized-elements

This article has been submitted by Leeni Joshua of ICON plc

Introduction:

Digital Data Flow (DDF) provides a mechanism to modernise clinical trials, facilitating a digital workflow that enables the automated generation of study elements and configuration of study systems to support the execution of clinical trials.

DDF initiative supports the creation of a digitised protocol that can be used by the downstream systems involved in the execution of the clinical trial. As a result, this enhances the flow of clinical information by improving its quality and relevance, while ensuring traceability across systems. Consequently, it leads to enhanced and optimised processes throughout the entire life cycle of the clinical trial.

The Role of ePRO in Clinical Research:

Patient-Reported Outcome (PRO) measures play a crucial role in clinical research, providing information that formsthe basis for decisions related to study design. The increasing adoption of electronic Patient-Reported Outcomes (ePRO) has transformed the landscape of data collection in clinical research, enabling traceability, automated dataflow and interoperability between systems.

This article explores the integration of DDF with both upstream and downstream processes in the context of ePRO, highlighting the challenges faced and the advantages gained in leveraging DDF as a foundation for data exchange, leading to greater compatibility among systems, flexibility to sponsors, and improved clinical trial efficiencies.

Interconnected Processes with DDF:

The upstream and downstream processes in DDF are interconnected using a common, industry-standard StudyDefinition Repository (SDR). DDF uses these standards to digitise the information related to major protocol components such as study information, study objectives, endpoints, inclusion/exclusion criteria, schedule of activities, and more.

By establishing a lineage between the Schedule of Activities, visit information, and data definition in a Metadata Repository, it becomes possible to automate the study build process in EDC and generate Data Transfer Specifications for ePRO.

Integration of DDF with these processes encounters challenges such as standardising diverse data inputs. For example, instruments like the Patient Global Impressions scale or the Pain intensity scale, which are in the public domain, do not have a single standardized version. This is due to the inclusion of the specific disease/condition, signs related to the disease/condition, function, and/or functional impact of interest within the wording of the global item; Additionally, the response options on these instruments vary and have not yet been standardised.

Questions also emerge in ensuring compliance with existing regulatory standards such as the CDISC controlled terminology. The test concepts and codelists assigned to questionnaire items in the SDTM terminology and SDTMIG supplements are typically derived from traditional paper versions. However, Issues may arise when items from the ePRO system are submitted differently due to programmatically derived or concatenated data. These issues can result in downstream errors, specifically with Pinnacle 21 (P21) validation rules.

Nonetheless, since DDF is agile and vendor agnostic, any product or platform capable of consuming data in a CDISC standard format can be easily integrated into the digital data flow and accommodate any change in standards, minimising the impact on ongoing trials and reduce the cost in change management.

Transformative Impact of DDF Integration:

Most PROs are standardized tests that is of Classical Test Theory (CTT), which are composed of a fixed number of items – that is, a question and its associated response scale and results in summed scores and requires respondents to complete the entire test for comparability. While they may be simple to administer, it may lead to increased burden due to the quantity of questions required to be answered, especially when the subjects are asked to complete multiple PROs together. Computerized adaptive tests (CATs) instead, use a variable number of items selected from a larger set of items, also known as an item bank. The item bank typically provides information across the full range of severities of a particular concept of interest, for example, physical function. Each subsequent item is selected based upon the responses provided to all the previous items. In this way, the response to each subsequent item becomes more focused and precise, leading to a higher level of confidence in the final estimate or score of the concept being evaluated. When sufficient confidence in the reliability of the estimate is achieved, the test can stop, and no further questions are required.

DDF opens doors to create end-to-end lineage and automated information flow between the clinical protocol and the downstream ePRO systems, thereby using advanced analytics such as IRT in CAT to enhance the optimisation of study design and refining analysis populations, scheduling of activities, patient engagement and operational efficiencies.

Addressing Technical and User Challenges:

The implementation of electronic clinical systems can be challenging in general, and ePRO systems are particularly susceptible to difficulties. In addition to facing typical technical issues, ePRO is also used by potentially thousands of study participants, many of whom may have limited technical understanding. Therefore, to ensure that all trial participants are included, the implementation of ePRO systems may need to be done in parallel with existing paper PRO collection systems.

Conclusion:

In summary, the integration of DDF with upstream and downstream processes involving ePRO presents challenges,particularly those related to regulatory compliance, technology barriers and costs of change management. However, it is important to consider these concerns within the context of early adopters’ success and the increasing interest and support from the FDA.

The effective integration of DDF not only improves data quality and integrity but also accelerates processes, empowers decision- makers, and contributes to advancements in patient-centric clinical research.