Director, Industry Strategy, Oracle Health Sciences

Elvin Thalund

 in the number of clinical trials and clinical trial applications. In an effort to reverse this trend, the EU has enacted a new clinical trial regulation—EU 536/2014, that greatly simplifies and enforces one clinical trial application process, to foster greater innovation and more trial applications.

While it presents a great opportunity to expand the clinical trial landscape, the new regulation also represents a huge shift in study planning and preparation—a shift that could lead to excessive delays and millions in lost revenue if not managed accordingly. Previously, each EU country had their own laws for clinical trial regulation. This meant more than 100 regulatory and ethical submissions across 30 countries (27 EU members and 3 conforming states) involved in setting up a study, which created obvious issues and bottlenecks. The new regulation greatly streamlines this process, but at the expense of content and timing flexibility. Now, any missing content about any investigative site in the submission could delay the trial enrollment by months.

To combat these challenges and realize the opportunity EU 536/2014 offers, sponsors and CROs alike need to rethink their approach to clinical trials.

January 2022 kicked off a three-year transition period in which the clinical trial directive, the existing process for handling submissions, will still apply for any studies underway. Companies will have a one-year grace period, during which initial clinical trial applications can be submitted under the new regulatory infrastructure but do not have to be. However, beginning in January 2023, all new submissions must be submitted under the new regulator infrastructure, and all ongoing studies have until January 2025 to either complete or convert to the new regulation.

Some organizations will no doubt want to submit under the new regulation right away to experience the system, likely testing it out on early-stage trials. Given the typical 6 to 8 months needed to ready a study, mid-2022 (now!) is the crucial deadline for all companies to prepare for the new regulation and the January 2023 deadline.

Overall, this new regulation establishes a thoughtful process from the very beginning and ensures high quality of and a more predictable timeline for studies. Until now, patient enrollment tasks could be planned and managed independently with minimal coordination between study, country, and site project managers. The focus has been on the first activity (e.g., first country and site approved) knowing additional activities would follow. This has allowed for decentralized planning and management, with only oversight for global and EMEA project managers.

With EU536/2014 all of the planning has to be done as one phase, and there are only two key parts to the submission process—Part I (study content) with the reporting country and Part II (country and site content) with the member states concerned. It has gone from 100+ submissions to just one, however, Part I and II are now fixed and aligned. This gives organizations clear timelines, but this alignment also means that the study startup is much less agile, as new sites can only be added four times a year. This strictly timed, single submission process is a paradigm shift that will require a great deal more up-front planning and coordination.

The role of machine learning in driving the process

As organizations try to manage this paradigm shift, having siloed systems and disparate data will be impossible given the need for upfront coordinated planning. To be successful, systems with underlying data structures must be coded, normalized, and de-identifiable. This will enable the application of advanced analytics and machine learning, which in turn, produces early, fast, and accurate insights for project management for submission.

Automating trial builds can minimize obstacles like protocol quality, human errors, and other issues that ultimately delay getting drugs/therapies to market. For example, using machine learning, systems can review all available historical data quickly and efficiently, uncovering all the problems created from prior protocol changes to fully optimize protocol design and building—ensuring steps aren’t missed and past problems aren’t repeated.

The new regulations provide an immense opportunity for organizations to be much more strategic with their planning. First, the thoughtful move to upfront planning will enable organizations to take a streamlined and holistic view of the planning process. Second, machine learning will give scientific insight into which indicators have the most impact on these models, so organizations can focus on those indicators to refine their models and learn from these insights. Ultimately, these changes can drive organizational and behavioral changes, such as earlier accurate predictions and less reliance on later subjective decisions, to optimize business processes. This can allow organizations to continuously improve and have a direct impact on timelines and associated costs of clinical trials. Now is the time to move ahead and embrace the opportunity EU536/2014 brings to clinical trials.

, director, industry strategy, Oracle Health Sciences

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New regulations offer opportunity for simplification in strategic planning.

The Challenge and Opportunity Presented by Clinical Trial Regulation EU 536/2014 

	Testing the safety and efficacy of new drugs is a costly and complex process for pharmaceutical organizations. The rising cost and complexity compromises profitability and can stifle research and innovation. Adding to that frustration is the fact that technologies companies use for specific phases of a clinical trial, such as clinical trial management (CTMS) and trial master file (TMF) systems, cannot be applied to the other phases. The fact is, there is no single magic pill that can accelerate clinical trials.

	The initial wave of technology tools focused on the clinical study conduct phase, after subjects were enrolled in the study. Systems that came out of this included CTMS as well as interactive voice response systems (IVRS) and electronic data capture (EDC) systems. Today, 100 percent of large pharma, 80 percent of small to mid-sized sponsors and 42 percent of CROs, use a CTMS.

	Many organizations have also started implementing technology for the IP approval submissions after closeout phase of the trials process. One-in-five CROs is currently using an eTMF application, while about 44 percent of sponsors are doing so

	CTMS and eTMF are specialized systems of critical importance, but neither looks at end-to-end improvements in clinical trials, especially in the early stages of study startup.   ETMS, eTMF along with purpose-built study startup represent the eClinical stack. Each tool-eTMF, CTMS, and study startup (SSU)-plays a distinct role in optimizing the full clinical trials process; each performs separate functions but serves overlapping user groups.

eTMF: document management for audit-ready documents 

	To comply with government clinical trial regulatory requirements, organizations are required to securely maintain and store essential documents. This information is typically stored in a trial master file, or TMF, which historically was comprised of paper documents stored centrally in physical file cabinets. In an attempt to lower costs and expedite the approval processes, the EU in created directives which led to the development of the eTMF. Relying on an eTMF for all documents is a mistake because it simply cannot provide sufficient project management capabilities.  

	While eTMF systems allow study teams to exchange, review, and archive documents, they cannot track the low-level tasks leading to critical activities and milestones. eTMFs are limited to document control which reflects only 80 percent of startup activities (e.g., country and study-specific SSU requirements).

CTMS: clinical trial execution and logistics 

	A CTMS provides operational awareness to the clinical operations department to help manage all aspects of the trial process. CTMS solutions were built to be all encompassing, but over time the clinical trial space became too complex to model in a single system. Other functions started popping up that required purpose-built architectures. In response, CTMS solutions broke off some of these functions into modules of a monolithic CTMS, such as the medicinal product dictionary, planning, or finance.

	A primary limitation of using CTMS as a single management tool is its reliance on outside systems and transcription from documents for its data, which prohibits the ability to provide accurate and reliable data for regulatory reuse and provide progress and real-time performance metrics out of the box. This hampers the ability of CTMS to drive extremely time-sensitive and complex parts of a clinical trial, including study startup.

Study startup: the fastest road to first patient in 

	The process leading to site activation is complex. It requires sponsors to select sites, negotiate contracts, fund and staff the trial, gain ethic committee and regulatory authority approvals in accordance with varying global requirements, obtain supplies of the drug to be tested, and comply with pre-enrollment regulations. Most pharmaceutical companies still track these site activation tasks and documents using email, spreadsheets, shared file drives, or homegrown applications, making it difficult to track the overall status of the project.

	Historically the study startup process does not help companies manage SOPs, accomplish critical milestones, meet contractual commitments, and compare sites efficiencies, and cycle times. Overall, it is hard to activate sites on time and budget, especially on a global basis where the laws and requirements may vary.

	Pharmaceutical companies are increasingly implementing study startup applications that are purpose-built to enable sponsors, CROs, and sites to get clinical studies started in the shortest time possible. Study startup applications support communicating, reporting, tracking, oversight, and data management to speed study teams through activation, while also reducing time spent assembling and discussing status updates.  All stakeholders view information in real time and have one single view of the truth.

	Study startup differs from CTMS and eTMF in its ability to automate not only document workflows but also activities, in order to analyze activation cycle times and suggest processes that are more efficient. For example, keeping content that is not ready for inspection out of the TMF provides tracking of the transactional process before critical points are reached. This allows companies to adapt and make adjustments to hold schedule.

	Integrating and automating the exchange of information between study startup, CTMS, and eTMF can provide efficiency gains and cost savings, but companies need to be pragmatic about systems integration and which system should own specific records. The system that owns the data (the system of record) should “talk to” the other systems that use it so that users don’t waste time and possibly commit errors because they have to re-enter data.

	It is imperative that pharmaceutical companies look at the overall process, identify where specific tools can help, determine how those tools interrelate, and implement good information governance across the eClinical stack. To keep costs low, maximize competitive advantage, and to deliver life-saving therapies to patients as quickly as possible the pharmaceutical industry must leverage technology to accelerate clinical trials.

Rob Wynden PhD, VP of Technology and Engineering and Elvin Thalund, Information Architect  

 Bio-IT World eCliniqua CTMS Survey Results, January 2015

 TMF Reference Model: Topline Results of 2014 TMF Survey #4, Fran Ross, August 2014

Understanding the roles of eTMF, CTMS, and study startup solutions in the clinical trials process

Elvin Thalund

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The Challenge and Opportunity Presented by Clinical Trial Regulation EU 536/2014

Speeding Clinical Trials Through eClinical Systems