Innovation in Clinical Trials: The CTIS Multi-Stakeholder Platform

This document explores the transformative impact of the Clinical Trials Information System (CTIS) multi-stakeholder platform on driving innovation in clinical trials across the European Union. We will examine how this centralized platform is simplifying, automating, and digitizing core R&D processes, advancing next-generation data analytics and technology to enhance clinical trial speed, quality, safety, and data integrity. The document covers the regulatory context, the benefits of the CTIS platform, its impact on various stakeholders, and the broader implications for clinical research and pharmacovigilance in the EU

Regulatory Context: EMA's Strategy and EU Initiatives

The European Medicines Agency (EMA) has developed a comprehensive regulatory science strategy for 2025 to address the rapid pace of innovation in healthcare. This strategy aims to tackle the challenges posed by increasingly complex medicines, growing real-world evidence, and emerging technologies. It builds upon the implementation of the Clinical Trials Regulation (Regulation (EU) No 536/2014) and aligns with broader European initiatives.

These initiatives collectively support the broader goals of the European Medicines Regulatory Network (EMRN) strategy to 2025 and the European Commission's Pharmaceutical Strategy for Europe. The introduction of the Clinical Trials Information System (CTIS) provides a central multi-stakeholder platform that serves as the data and technology backbone for this transformation across the EU/EEA.

The R&D Productivity Challenge

The pharmaceutical industry has faced significant challenges in Research & Development (R&D) productivity over the past decade. These challenges are characterized by pipeline attritions, extended development timelines, and increasing costs of clinical trials. While the COVID-19 pandemic has been an outlier in terms of accelerated development, the overall trend remains concerning for the industry.

Despite these challenges, the industry has delivered many life-changing therapies for various diseases through novel therapeutics. However, the complexity of these innovative therapies requires careful management, particularly as medical devices, in vitro diagnostics, and clinical trial regulations increasingly overlap. This is evident in the rise of decentralized trials, single-arm studies, and combined trials.

The industry is now focusing on alternative productivity measures and changing its innovation approach. There's an increasing emphasis on developing 'blockbuster' and 'mega-blockbuster' drugs to offset R&D investments. However, this strategy faces headwinds from policy changes such as the Inflation Reduction Act in the US and increasing biosimilar penetration due to patent expiries.

Promoting Speed and Transparency in Clinical Trials Safety Communication

The clinical trial landscape is undergoing a strategic transformation across all regulatory bodies and the broader healthcare ecosystem. This transformation is driven by several key factors that are reshaping how clinical trials are conducted, monitored, and communicated.

A key development in this transformation is the recognition of health data as a new currency driving innovative solutions to address growing healthcare challenges. The EU Health Data Space initiative is a prime example, allowing for the exchange of electronic health records, genomics data, and disease registries while ensuring data privacy. This is further supported by the EU Data Governance Act, which lays out rules for data reuse and sharing, with data intermediaries acting as service providers.

The EMA EU Telematics strategy is paving the way for EU regulatory master data, governance, interoperability, digitization, and regulatory innovation. This strategy aims to increase quality, speed, and collaboration in the regulatory process. As clinical trial designs evolve, we're seeing an integrated end-to-end journey between development, post-market, and real-world data generation, creating a connected loop that enhances our understanding of drug safety and efficacy.

EU Clinical Trials Regulation and the Centralized Multi-stakeholder Platform

The European Union has been transitioning from the EU Clinical Trials Directive (CTD) to the EU Clinical Trials Regulation (CTR) since January 2022. This shift represents a significant change in the regulatory framework for clinical trials across the EU, moving from a complex and siloed system to a single, harmonized regulation.

The Clinical Trials Information System (CTIS) is at the heart of this transformation, offering a centralized platform for all stakeholders involved in clinical trials across the EU. Since its launch in 2022, CTIS has processed 2,441 Clinical Trial Application (CTA) submissions, with approval timelines averaging 90 calendar days for 761 initial clinical trials applications over a specific period. These metrics indicate that the system is meeting the EMA's aspirations for efficiency and stakeholder engagement.

The EU CTR necessitates significant changes to processes, roles, and safety communications linked to clinical trials management. It aligns with the EU's central data strategy and streamlines regulatory activities in conjunction with EU SPOR (Substances, Products, Organisations and Referentials) data management, creating an interface across regulatory, clinical, and safety domains. For safety specifically, there are key changes in definitions, data requirements for electronic submission of Suspected Unexpected Serious Adverse Reactions (SUSARs), Annual Safety Reports (ASRs), and ongoing communication between sponsors, EMA, and Member States via CTIS.

CTIS Public Module: Enhancing Transparency and Access

In alignment with the EU's transparency policy, the CTIS Public Module represents a significant step forward in providing access to clinical trial information. This module allows the general public, including patients, healthcare professionals, and researchers, to access the latest information on clinical trials conducted in the EU, while adhering to EU data privacy requirements.

The implementation of the CTIS Public Module necessitates that sponsors redesign their operating models and strategies. This redesign should enable internal functions to establish a central platform where multiple departments (e.g., Clinical, Safety, Regulatory) and external partners (e.g., Contract Research Organizations) can orchestrate transversal processes and exchange study data efficiently.

A critical aspect of the EU CTR is the mandate for speed and quality of submissions. Low-quality submissions risk rejection, potentially requiring resubmission and halting study activities across the EU/EEA. This emphasizes the importance of adopting a 'right first time' mindset, where sponsors must consider the end-to-end process upfront. The new 12-day request for information period for additional document submission, including redacted versions, adds further pressure to ensure successful submissions from the outset.

Early adoption experiences across the industry have highlighted this as a major pain point, underscoring the need for thorough preparation and streamlined processes to meet these new regulatory requirements effectively.

Pharmacovigilance Impact Assessment for Sponsors

The implementation of the EU Clinical Trials Regulation (CTR) has far-reaching implications for the entire value chain of clinical trials management. For sponsors, the impact's magnitude depends on several factors, including the total portfolio of trials, the overlap between EU/EEA and third-country trials with EU reporting obligations, and other study design risks such as complex therapeutic areas or safety profiles.

The introduction of Low Interventional Trials presents an opportunity for sponsors and non-commercial organizations to incorporate this new classification into their processes, potentially reducing the burden of safety reporting for certain types of studies. However, the introduction of new Auxiliary Medicinal Products (AxMPs) may increase complexity and reporting burden for some sponsors, particularly in multi-arm studies or trials involving multiple IMPs and AxMPs.

For pharmaceutical companies, an impact assessment of the Pharmacovigilance Agreements with their Non-Commercial Clinical Trials Sponsors will also be required to revise the necessary safety data exchanges aligned to EU CTR. The roles for Safety Aggregate Report and Clinical Safety Management teams will need to be clearly defined upfront to ensure smooth operations under the new regulatory framework.

Rethinking Clinical Surveillance Strategy

The EU Clinical Trials Regulation (CTR) has established a coordinated work-sharing approach for monitoring clinical trial safety and improving the quality of safety data in trials. This introduces a comprehensive centralized expert committee review where Member States work together, aligned with the EU4Health Joint Action Safety Assessment Cooperation and Facilitated Conduct of Clinical Trials (SAFE CT).

This increased focus on coordinated clinical safety across the EU impacts how industry manages the exchange of regulatory, clinical, and safety data from study setup through conduction and closeout. Real-time communication via CTIS, including stringent timelines for Health Authority communication through Requests for Information, is putting pressure on sponsors to streamline internal coordination.

Communication between Member States and sponsors will be via CTIS (ASR, ad hoc assessment, corrective measures) with strict timelines for responding to Health Authority Requests for Information within 12 calendar days. Failure to comply with these timelines will result in withdrawal in all Member States Concerned. The speed of bidirectional data flow requires safety to be an integrated technology platform with well-orchestrated processes across R&D (e.g., regulatory, clinical teams, and partners).

As with the introduction of the Pharmacovigilance Risk Assessment Committee (PRAC) for post-market safety and real-time publication of safety signals and other public health measures, the Qualified Person Responsible for Pharmacovigilance (QPPV) and industry face an increased workload to manage queries from Health Authorities, as well as patients and the public. A similar trend can be expected within the clinical safety surveillance areas.

EU CTR Readiness: Key Considerations for Pharmacovigilance

As organizations prepare for full compliance with the EU Clinical Trials Regulation (CTR), it's crucial to assess the readiness of the pharmacovigilance function. Here are some key considerations to help prepare your pharmacovigilance operations:

Additionally, consider the impact on pharmacovigilance oversight and reporting obligations aligned with business partners and investigator-initiated trials. Review and update Safety Data Exchange Agreements (SDEAs) as necessary. Don't forget to update reporting obligations within your Pharmacovigilance System Master File (PSMF) annexes to reflect the new regulatory requirements.

Finally, make strategic, risk-based decisions across R&D to streamline and maximize the opportunity to simplify processes and data submissions. For example, consider how to leverage the new category of low-interventional studies to potentially reduce the burden of safety reporting for certain trials.

Integrated Clinical Surveillance Strategy

As the landscape of clinical trials evolves under the EU Clinical Trials Regulation (CTR), there is a growing need for an integrated clinical surveillance strategy. This strategy should encompass the entire lifecycle of a medicinal product, from early development through post-marketing surveillance, creating a seamless flow of safety information.

The integrated clinical surveillance strategy should address the increased focus on coordinated clinical safety across the EU. This includes managing the speed of bidirectional data flow, which requires safety to be an integrated technology platform with well-orchestrated processes across R&D (e.g., regulatory, clinical teams, and partners).

Organizations need to consider how the orchestration of Development Safety, Authorization and Commitments, and Post-Market Safety will be integrated in real-time for products that have an active portfolio of clinical programs and post-market activities. This integration is crucial for maintaining a comprehensive view of a product's safety profile throughout its lifecycle.

The strategy should also account for the increased workload in managing queries from Health Authorities, patients, and the public, similar to the trend seen with the introduction of the Pharmacovigilance Risk Assessment Committee (PRAC) for post-market safety. This may require additional resources and refined processes for timely and accurate response to inquiries.

By implementing an integrated clinical surveillance strategy, organizations can ensure they are well-prepared to meet the challenges and opportunities presented by the EU CTR, while maintaining the highest standards of patient safety and data integrity in clinical research.

Technology and Data Management Implications

The implementation of the EU Clinical Trials Regulation (CTR) and the Clinical Trials Information System (CTIS) brings significant implications for technology and data management in the pharmaceutical industry. Companies must adapt their existing systems and processes to meet the new requirements for data submission, management, and sharing.

One of the key challenges is the need for real-time data exchange between various stakeholders. This requires robust, interoperable systems that can securely transmit and receive data in compliance with CTIS requirements. Companies may need to invest in new software solutions or significantly upgrade existing ones to meet these demands.

Data standardization becomes crucial in this new environment. With the requirement to submit data to a centralized system, ensuring data quality and consistency across different trials and sites is paramount. This may necessitate the implementation of standardized data collection and management processes across the organization.

Another important consideration is the management of data privacy and security. With increased transparency and data sharing comes the responsibility to protect sensitive information. Companies must implement stringent data protection measures and develop clear protocols for data redaction when submitting information to the public module of CTIS.

Lastly, the shift towards more transparent and accessible clinical trial data presents opportunities for advanced analytics and data science applications. Companies that can effectively leverage this wealth of data may gain competitive advantages in drug development and clinical trial design.

Future Outlook and Recommendations

As the pharmaceutical industry continues to adapt to the EU Clinical Trials Regulation (CTR) and the Clinical Trials Information System (CTIS), several key trends and recommendations emerge for the future of clinical trials and pharmacovigilance in the EU.

Looking ahead, organizations should focus on building agile systems and processes that can adapt to evolving regulatory requirements. This includes not only technical systems but also organizational structures that promote collaboration between clinical, regulatory, and safety teams.

There's also an opportunity to leverage the increased transparency and data sharing facilitated by CTIS to drive innovation in clinical trial design and execution. Companies that can effectively analyze and learn from the wealth of publicly available trial data may gain significant competitive advantages.

Furthermore, as the EU continues to lead in clinical trial regulation, it's likely that other regions will follow suit. Organizations should consider their EU CTR compliance efforts as part of a broader global strategy for clinical trial management and pharmacovigilance.

In conclusion, while the transition to EU CTR and CTIS presents challenges, it also offers opportunities for improving the efficiency, transparency, and ultimately the effectiveness of clinical trials. By embracing these changes and proactively adapting their operations, pharmaceutical companies and research organizations can position themselves at the forefront of clinical research innovation in the EU and beyond.