The second event in our series of C3 Summits took place in Boston on May 16, 2023. We invited industry experts and leaders to discuss challenges, opportunities, and strategies in clinical trial diversity, centricity, and outcome assessments through the lens of real-world experience. In this recap of the Boston session, we will review key points from each session.
Session 1: COA/eCOA Innovations – Licensing Hiccups, Linguistic Validation, ePRO Migration, and Best Practices to Ensure First-Patient-In
- The importance of paper backups: Despite the prevalence of electronic systems for patient data capture, paper backups are still necessary for continuity in case of technological failures or compliance with copyright holders' requirements.
- Operational challenges of incorporating paper backups: Integrating paper backups into electronic systems presents challenges, including resistance to transitioning fully to electronic processes and the complexities of reconciling data from different sources, requiring meticulous attention to avoid discrepancies and data loss.
- Unique challenges in rare disease studies: Rare disease studies face additional difficulties in gathering patient data due to factors such as small and dispersed patient populations, language barriers, licensing constraints, and reliance on parents and caregivers for compliance. Ensuring patient adherence to protocols is crucial, and a hybrid approach combining paper backups and electronic systems can encourage compliance and meaningful data while balancing data security concerns.
In the rapidly advancing digital age, electronic systems and modalities for patient data capture have become the norm, offering convenience and efficiency across various industries, including healthcare and research. Perhaps more importantly, it has given us more accurate, usable patient data. However, many cases still require a paper backup. In this session, we explored the continual relevance of paper backups, their associated challenges, and the potential for hybrid models.
While electronic modalities are demonstrably more efficient and accurate, certain circumstances, such as a catastrophic technological failure, can render these systems inaccessible, making a paper backup crucial for continuity. Furthermore, some copyright holders still rely on paper documentation, necessitating a paper trail for compliance.
However, incorporating paper backups into electronic systems presents operational challenges, including the reluctance to fully transition from paper to electronic processes. Local disasters or device malfunctions can also render electronic devices unusable, necessitating a paper backup. Reconciling and aligning data from different sources becomes complex and time-consuming, requiring meticulous attention to avoid discrepancies and data loss.
Furthermore, obtaining electronic instrument and systems licenses can delay timelines and present additional operational challenges. Factors such as high demand or limited availability of licenses can compound these issues and cause further delays. Regulatory requirements, such as translation licensing and study changes, can create unexpected bottlenecks. This is especially true in the case of international rare disease studies, particularly when new patients enter the study from different regions.
As a result, rare disease studies face unique challenges in gathering patient data. The small and dispersed patient population, language barriers, licensing constraints, and reliance on parents and caregivers for compliance further complicate the process. Ensuring patient adherence to protocols is crucial for collecting meaningful outcomes and demonstrating the value of research to the rare disease community. This is compounded by the challenge of enrolling such a small patient cohort; the patient data is more valuable in some ways.
Therefore, incorporating a hybrid approach of both paper backups and electronic systems is perhaps necessary for driving patient adherence. This approach accommodates patients who prefer paper backups or lack access to personal devices, and it encourages compliance and meaningful data. Hybrid models can also mitigate data security concerns by implementing biometric authentication on personal devices, thereby balancing patient convenience and data integrity.
Nonetheless, stakeholders must address licensing, translation, instrument change, and regulatory compliance challenges. Collaboration, streamlined processes, and ample lead time can make a significant difference. Proactivity in the planning phase is critical for translation and licensing. Initiating the licensing process early and finalizing custom-built instruments before selecting a vendor or during feasibility stages remove potential bottlenecks and facilitate progress.
Collaboration from all stakeholders is also essential. Involving supporting vendors, translation teams, and localization experts during protocol development establishes a framework for more effective communication. Sponsors and study teams should remain aligned on instrument changes with a mutual understanding of the risks associated with design alterations. By bringing together all key stakeholders early in the process and fostering a collaborative environment, study teams can address and mitigate challenges more effectively. It was universally agreed that engaging all stakeholders, both internal and vendor partners, early in the planning process significantly increases first-patient-in (FPI) goals.
Session 2: Patient Recruitment and Inclusivity – Engagement Strategies for Diversity and Accessibility
- Importance of patient engagement: Patient engagement plays a crucial role in the success of clinical trials even before they begin. Understanding patients' lived experiences helps determine reasonable protocol criteria and assessment schedules, and tailoring communication strategies effectively enhances participation.
- Bridging gaps for inclusivity: Acknowledging diverse cultural and socioeconomic backgrounds allows study teams to identify and bridge gaps in access, language barriers, and scheduling challenges faced by underrepresented populations. Inclusivity generates a more accurate portrayal of drug efficacy and ensures equitable access to treatment.
- Technology and patient engagement: Mindful algorithm development, targeted simulations, and designing technology platforms with inclusivity in mind can bridge digital disparities and improve engagement. Recognizing individual preferences and providing flexible compensation models empower patients and promote long-term engagement and retention.
Patient engagement impacts clinical trial success before a clinical trial even begins. Study teams must understand and appreciate patients’ lived experiences to determine if protocol inclusion/exclusion criteria and visit assessment schedules are reasonable.
Understanding patients' backgrounds allows researchers to tailor their communication strategies effectively. For example, commonly used terms, such as “investigator,” “trial,” and “consent,” may carry negative legalistic associations, making patients less likely to participate. Acknowledging diverse cultural and socioeconomic backgrounds provides a more holistic assessment of the challenges faced across different communities. From this understanding, study teams can identify where these gaps can be bridged to maintain engagement.
Challenges may include a lack of access to certain technologies, language/accessibility barriers, or navigating site visits around work/family schedules. While driving inclusivity may command additional resources to accommodate specific patient needs, engaging diverse demographics generates a more accurate portrayal of drug efficacy. Therefore, in the interest of a comprehensive public health model and equitable access to treatment, underrepresented groups must receive proper representation throughout a clinical trial.
Technology can potentially enhance the recruitment, retention, and engagement of underrepresented populations. However, it is essential to be mindful of the digital divide, ensuring equitable access and providing necessary resources and support to afford patients equal opportunities. Furthermore, leveraging technology and digital innovation should be balanced by mindful algorithm development and targeted simulations to reduce bias and improve inclusivity. Designing technology platforms with patient inclusivity in mind and utilizing familiar channels can help to bridge digital disparities and enhance engagement.
In addition to ensuring equitable access to digital tools, recognizing individual preferences, motivations, and compensation options empowers patients and promotes long-term engagement and retention. Flexible compensation models and incentives allow participants to choose rewards that resonate with them.
Regulatory guidance, such as the FDA's focus on diversity in clinical trials, encourages industry stakeholders to prioritize inclusivity. Pre-engagement strategies, comprehensive patient selection, and addressing broader healthcare and wellness issues contribute to building trust and achieving meaningful results. Continued progress requires accountability, tangible actions, and prioritizing diversity in all aspects of healthcare.
Section 3: Remote Study Team Engagement – Patient Safety, Site Accountability, and Clinical Document Quality
- COVID-19 impact: Limited resources and staff shortages have slowed clinical trial progress while innovations have emerged to engage patients and minimize infection risks.
- Expanded reach and decentralization: new sites in diverse regions mitigate resource constraints, and feasibility studies determine opportunities for remote options and best practices sharing.
- Proactive engagement and technology integration: Sponsors should support sites, provide incentives, and connect with recruitment agencies to drive engagement early in the process. Technology, including virtual communities and wearables, enhances patient engagement and real-time data collection while facilitating effective communication among study team members. Maintaining trial integrity is vital, balancing accessibility with data quality and patient safety.
In recent years, the impact of the COVID-19 pandemic on various stages of clinical research has become apparent. Limited resources at clinical trial sites have resulted in slower site response times and engagement. Additionally, a shortage of qualified individuals, including sponsors and contract research organizations (CROs), has further hindered trial progress. The vacancies left from staff changes were slow to be filled, leading to increased contract review timelines and reduced recruitment momentum. Challenges were also associated with having patients present at trial sites, with many avoiding healthcare facilities entirely in an effort to reduce exposure. However, these challenges bred innovations to facilitate ongoing and future trials with minimal interruption, with researchers identifying new ways to ensure they can engage patients while also minimizing the risk of infection.
The introduction of new sites in different regions during the past few years has also expanded the reach of clinical trials and mitigates resource constraints. Engaging with sites in diverse countries and conducting regional investigator meetings ensures culturally appropriate messaging and facilitates the sharing of best practices. Feasibility studies play a crucial role in determining-
One critical takeaway is the importance of proactive engagement with clinical trial sites. Sponsors should understand the needs of different sites and offer support to strengthen the sponsor-site relationship and alleviate the burden on trial site personnel. In terms of resource building, sponsors may introduce incentives, such as sponsoring conference attendance for study coordinators, subsidizing continuing education for site personnel, and providing grants for necessary equipment. These measures address specific site needs and create a sense of reward and appreciation for their contributions. Connecting sites with recruitment agencies can also help alleviate remaining staffing challenges. Facilitating introductions between various agencies and sites allows for the identification of suitable local talent, easing the strain on site personnel.
Throughout the transition to remote trials, technology has been a cornerstone in ensuring smooth, ongoing operations. It has provided flexibility for clinical trial participants to communicate with healthcare professionals without in-person visits, reducing travel burdens and potential exposure. Technological advancements, including virtual patient communities, wearable devices, and mobile applications, enhance patient engagement, enable real-time data collection, and facilitate remote monitoring. Leveraging collaborative project management tools, virtual meetings, and webinars enables effective communication, knowledge sharing, and collaboration among study team members, regardless of their physical location. As we continue to move into a decentralized clinical landscape, we will continue to see innovations simplifying processes for both patients and research staff alike. Furthermore, there is the expectation that regulatory authorities will begin providing more refined guidance on leveraging clinical technologies and data capture/security.
While decentralized clinical trials (DCT) have the potential to make trials more accessible and patient-centric, maintaining trial integrity is crucial. Recent FDA guidance on DCTs emphasizes the importance of balancing accessibility with data quality and patient safety. Active engagement with sites, tailored support, streamlined processes, and technology integration enhance remote study team engagement. Building strong relationships between sponsors and sites ensures efficient clinical trials, advanced medical research, and improved patient care.
Session 4: EU Clinical Trial Regulation – Operational Considerations and Impacts
- EU Clinical Trial Regulation (EU CTR): Organizations conducting trials in the EU need to understand the new regulatory framework, transition from the previous regimen, and comply with new requirements. This includes updating quality management systems, understanding the EU portal, and ensuring streamlined submissions and translations.
- Operational challenges with the EU portal: While the EU portal streamlines the application process, it may not fully address all user requirements, and managing multiple studies within the portal can be complex. Researchers should anticipate increased workloads and consider optimization strategies to expedite the handling of queries.
- Compliance and transparency requirements: The EU CTR emphasizes transparency and disclosure of trial information. Responding to queries within tight timelines requires a thorough assessment of translation processes, removal of confidential/personal data, and adherence to transparency requirements.
The field of clinical trial management witnessed a significant development with the introduction EU CTR. This regulation impacts various aspects of clinical trial management activities. Understanding the new regulatory framework and complying with requirements become crucial for organizations intending to conduct trials within the EU. When a trial is authorized under the previous regimen (CT Directive) and continues in Europe after January 2025, researchers will need to transition to the new regulatory framework. The transition requires submission via the new EU portal and may involve updating protocol or other study documents to ensure overall compliance with the new requirements. In all, the new regulation brings forth a litany of operational considerations, including updating your quality management system, understanding the EU portal, handling sensitive data (transparency/disclosure), and ensuring streamlined submissions and translation processes across the board.
One of the primary factors in rolling out the EU CTR was the development of the EU portal, a technical platform for submitting clinical trial applications. This enables researchers to complete a single application that is distributed to the relevant countries for assessment. This centralized submission process streamlines the application process but also introduces dependencies between countries' submissions. It is crucial to have all documents ready simultaneously to ensure timely initiation across all countries.
Despite a feeling of positive progress surrounding the EU portal, it has also brought operational challenges. The portal was initially released as a minimally viable product, and its functionalities may not fully address all user requirements. Additionally, managing multiple studies and administrative processes within the portal can be complex, and extracting information for higher-level master files may require additional effort. Therefore, it is essential to be prepared for the potential of increased workloads and consider optimization strategies, such as centralization or expedited handling of queries.
In relation to compliance activities, there is a legal requirement to respond to queries from ethics committees and regulatory authorities within 12 calendar days, leaving limited space for negotiation. Promptly answering queries necessitates document amendment, language translation, eventual redaction of confidential/personal data, and submission preparation, all within tight turnaround times. Therefore, research teams should thoroughly assess the readiness of translation processes and their articulation with redaction activities and ensure comprehensive approval processes to meet these requirements.
One key component of the regulation is transparency, as it emphasizes the disclosure of trial information to foster clinical research and enables patients to access relevant trial information and statistics. This means many of the documents submitted through the portal will be made public after a certain period. This may prompt changes to how researchers handle sensitive data, in that they should be meticulous in the removal or redaction of confidential/personal data from submissions before they are presented.
In cases where additional countries must be added to a trial following initial submission, the process will depend on whether the countries were already selected for participation in the trial (but not ready at the time of submission) or if they are new additions. If the countries are already part of the trial, you will need to complement your initial application with country-specific information to reach an initial decision for that country (with a review process to apply for the new country information). For newly added countries, you will need to submit an additional member state application to the existing submission. This application will go through a slightly different review process than the initial application, focused on the newly added country’s/countries’ information.
The Future of EU CTR
Despite intentions to streamline the clinical trial submission process, challenges have been and continue to be observed in the rollout of the new regulation in day-to-day operations. There have been numerous technical issues flagged with the new systems, and the lack of predictability creates uncertainties and potential delays. The European Medicines Agency (EMA) acknowledges these issues and plans to address them through ongoing development and optimization of the CTIS portal.
The European clinical trial submission process is still in its early stages, and further refinements are expected. Initiatives like the Act2 project aim to make Europe more attractive on political and regulatory levels. However, changes to the process and regulations will take time to fully implement. To that end, it is critical that stakeholders continue to engage in discussions, provide feedback, and contribute to shaping the future of the European clinical trial landscape through optimization and streamlined operations.
Under the EU CTR, stakeholders are being challenged with adapting to new procedures and technical requirements while carefully planning their submissions. Early inclusion of countries, active engagement with the EU portal, and compliance with timelines and transparency requirements are instrumental in ensuring successful submissions. As the system evolves and technologies are further refined for usability, the projection is that the European clinical trial landscape will become more efficient, transparent, and attractive for sponsors and researchers alike.
The C3 Summit focuses on relevant topics in the clinical space, including patient recruitment and leveraging AI in clinical technologies. Upcoming sessions include a focus on EU CTR, patient diversity, and eCOA. Interested in attending upcoming C3 Summit sessions in a city near you? Register today for our upcoming London or Princeton events to secure your spot to access exclusive expert insights and connect with industry peers.