[Image courtesy of Adobe Stock]
What advances in NGS technology have made it more accessible or practical for CROs to incorporate into trial designs?
Binh Nguyen, M.D., Ph.D.
Binh Nguyen, M.D., Ph.D.: One of the most significant improvements addresses the challenge of Quantity Not Sufficient (QNS) samples, with today’s NGS systems demonstrating remarkably high success rates in identifying patients with specific biomarkers, even from limited sample material.
The speed of analysis has advanced at an impressive rate, with current NGS technologies capable of delivering results in as little as 24 hours from specimen to report on the Ion Torrent Genexus Dx Integrated Sequencer. This rapid turnaround time is crucial for enabling timely enrollment in precision oncology trials, significantly reducing delays in trial enrollment and progression.
Cost-effectiveness has also improved substantially, particularly for smaller-scale projects. Modern NGS platforms now accommodate smaller batch sizes – as few as 16 samples – allowing for more flexible and efficient processing without sacrificing quality or accuracy. This capability enables faster result delivery while maintaining cost-effectiveness, making NGS accessible to more community-based and decentralized trial sites.
The technology’s ease of use represents another crucial advancement. Current NGS systems can be readily established in local laboratory settings with minimal staff training requirements, reducing the barrier to entry for many organizations. This simplified implementation process helps CROs integrate NGS capabilities into their existing infrastructure more seamlessly.
Instruments like the Genexus System also offer unprecedented versatility in sample analysis. They can perform complete DNA, RNA and cell-free tumor DNA (cfTNA) purification across a diverse range of specimen types. From formalin-fixed paraffin-embedded (FFPE) lysate to whole blood, bone marrow, peripheral blood leukocytes (PBL), fresh-frozen tissue and plasma, this broad compatibility ensures that CROs can effectively analyze virtually any relevant biological sample in their clinical trials.
What specific barriers in traditional clinical trial design are being addressed by incorporating NGS technologies?
Nguyen: One of the most significant challenges in traditional trial design has been the requirement for substantial tissue volumes for comprehensive biomarker analysis. This requirement has been particularly problematic when dealing with anatomically challenging locations where tissue acquisition is difficult or risky for the patient. NGS’s ability to generate meaningful results from minimal tissue samples has revolutionized this aspect of clinical trials, making it possible to conduct thorough analyses even with limited specimen availability.
A crucial advancement addresses the pressing issue of turnaround time in biomarker screening. In traditional trial designs, the extended waiting period for biomarker results has been more than just an inconvenience – it has been a critical limitation, especially for patients with advanced metastatic disease where time is of the essence. These patients require rapid treatment decisions, and any delay in biomarker screening results can significantly impact their care trajectory.
NGS technology has dramatically compressed these timelines, enabling faster treatment initiation that targets their specific tumor marker.
The financial burden associated with traditional central biomarker laboratory services has been another substantial barrier, particularly in trials focusing on rare mutations or rare cancers. In these cases, the screen failure rate can exceed 90%, making the conventional approach of shipping samples to central laboratories for testing both costly and inefficient. The expenses associated with sample testing and shipping have often strained research budgets, potentially limiting the scope and scale of clinical trials. NGS technology’s ability to provide comprehensive molecular profiling more efficiently and cost-effectively, especially when implemented locally, helps mitigate these financial challenges while maintaining high-quality results.
How do end-to-end partnerships that include NGS solutions accelerate the path to market for therapies?
Nguyen: A key advantage of these partnerships lies in the early integration of companion diagnostic (CDx) development alongside the therapeutic agent. This parallel development approach, enabling simultaneous drug and CDx submission and approval processes, represents a significant evolution from traditional sequential development models. By aligning these typically separate pathways, organizations can substantially reduce the overall time to market while ensuring that the diagnostic tool is perfectly matched to the therapy’s requirements.
The strategic selection of clinical trial sites with existing NGS capabilities has emerged as another crucial accelerator in the development process. These pre-equipped sites can begin patient screening and enrollment immediately, eliminating the delays typically associated with setting up new testing infrastructure or waiting for external laboratory results. This immediate readiness significantly streamlines the patient identification process, leading to faster trial enrollment and, consequently, earlier completion of clinical studies.
These integrated partnerships have also reduced study management complexity. Traditional clinical trials often involve coordinating multiple third-party vendors, each handling different aspects of the testing and analysis process. By consolidating these services through comprehensive partnerships that include NGS capabilities, sponsors can significantly reduce the administrative burden and potential communication barriers that often slow down trial progress. This streamlined approach not only accelerates the development timeline but also reduces the risk of delays or errors that can occur when managing multiple vendor relationships.
What challenges do CROs face when integrating NGS into their trial designs, and how can these be mitigated?
Nguyen: Complexity management and cost considerations are the primary hurdles, requiring careful navigation and strategic planning.
One of the most substantial challenges lies in the increased complexity of study management. This encompasses several interconnected elements that must be carefully coordinated. The management of third-party vendors requires meticulous oversight and clear communication channels to ensure seamless operation. Sample shipping processes demand precise logistics management, including maintaining appropriate environmental conditions and chain of custody documentation. Additionally, the resolution of any issues that arise during these processes must be handled swiftly to prevent delays in the trial timeline. The management of tissue block returns adds another layer of complexity, requiring careful tracking and coordination with multiple stakeholders to ensure proper handling and storage of valuable biological materials.
The financial implications of central biomarker laboratory services present another significant challenge. These costs can be substantial and multifaceted, encompassing both the direct expenses of sample testing and the logistics of sample transportation. The shipping costs alone can be considerable, especially when dealing with temperature-sensitive materials that require specialized handling and expedited delivery. These expenses can significantly impact trial budgets, particularly in studies involving multiple sites or requiring frequent testing.
To mitigate these challenges, CROs are increasingly adopting integrated solutions that combine local testing capabilities with centralized oversight. This hybrid approach can help reduce shipping costs and complexities while maintaining standardization across sites. Additionally, implementing robust digital systems for sample tracking and vendor management can help streamline operations and reduce administrative burden. Early planning and careful consideration of NGS integration during the trial design phase can also help anticipate and address potential challenges before they impact the study timeline or budget.
In what ways do you see the role of NGS expanding in the future to address emerging needs in drug development?
Nguyen: A critical challenge in current drug development landscapes is the limited availability of NGS testing facilities, especially in community settings and emerging markets. This limitation creates geographical and logistical barriers that can slow down clinical trials and restrict patient access to potentially life-changing therapies.
Trial decentralization represents a key strategy in addressing this challenge, with the movement of NGS capabilities from centralized laboratories to community oncology settings and rural or underserved areas. This shift is particularly crucial for ensuring broader, more diverse patient participation in clinical trials and accelerating the drug development process globally. The evolution of NGS technology, exemplified by user-friendly systems like Genexus, is making this decentralization increasingly feasible.
The accessibility features of modern NGS platforms – including simplified workflows, rapid turnaround times and minimal training requirements – are proving instrumental in this expansion. These characteristics make it practical to establish NGS capabilities in locations that previously lacked access to such advanced molecular testing.
This democratization of NGS testing supports faster, more inclusive precision medicine by reducing the need for patients to travel to academic centers for molecular screening. It also helps ensure equitable access to trials by enabling care teams in community and rural areas to identify eligible patients in real time.
Can you share any examples or case studies where NGS played a pivotal role in overcoming hurdles during clinical trial execution or enabled new approaches to trial design?
Nguyen: There was a global study focusing on non-small cell lung cancer (NSCLC), specifically targeting HER2-positive cases, which represent approximately 3% of all NSCLC cases.
The study faced several initial challenges common to precision oncology trials. Many NSCLC specimens were only available as fine-needle biopsies or needle aspirates, resulting in very small sample quantities that posed significant analytical challenges. Additionally, the traditional approach of sending samples to commercial labs for testing often led to delays in turnaround time, potentially impacting patient care and trial progress.
To address these challenges, we proposed implementing the FDA-approved Oncomine Dx Express Test, a highly sensitive, tissue-saving solution with rapid turnaround capabilities. This strategic choice proved particularly valuable for future CDx test development. The assay’s availability in decentralized local hospital settings proved crucial in accelerating patient identification and enrollment.
The implementation yielded several significant outcomes. The platform’s sensitivity helped identify more eligible patients and preserved precious tissue samples for CDx test development – a critical consideration in targeted therapy trials. Furthermore, by working across business units, we effectively cross-referenced known Oncomine sites with their proposed site list, enriching locations likely to identify the 3% of HER2-positive patients needed for the study.
This case study illustrates how strategic integration of NGS technology can not only overcome common trial execution hurdles but also enable more efficient, patient-centric trial designs through decentralized testing capabilities and rapid result delivery.
