In the early 21st century, the introduction of next-generation sequencing (NGS) technology ignited a transformative spark in the medical world. This groundbreaking method, known for its speed, efficiency, and cost-effectiveness, emerged as a beacon of hope for accurate DNA sequencing with profound implications for the diagnosis of cancer and various genetic disorders. However, with this innovation, challenges emerged, prompting a collaborative effort to realize the potential of using NGS for cancer diagnostics.
The FDA–NIH Joint Leadership Council (JLC) identified gaps to moving this technology toward widespread diagnostic applications in 2018. These gaps encompassed crucial aspects such as the lack of well-characterized somatic and germline samples, which hinder the validation of NGS testing and methodologies across laboratories. Additional challenges included the absence of infrastructure to support these materials, limitations in available tools for reference material analysis, and the need for a diverse range of appropriately consented and replenishable reference samples that represent the spectrum of potential variations and allele fractions of interest.
In response to these gaps, and recognizing the potential of this technology for disease management, the FDA envisioned a regulatory framework for NGS-based in vitro diagnostics (IVDs), calling for the development of reference sample sets to effectively validate NGS platforms.
The Somatic Reference Sample (SRS) Initiative
The launch of the Somatic Reference Sample (SRS) Initiative was a game-changing response to these challenges. Aligned with the FDA's vision, the SRS Initiative has emerged as a dynamic public–private partnership, convened by the Medical Device Innovation Consortium (MDIC). At its core, this initiative draws in the scientific community, uniting stakeholders to steer the creation of characterized reference samples and datasets. These resources are destined to fuel the development and validation of NGS-based cancer diagnostics, marking a monumental stride toward precision medicine.
Collaborators in the SRS Initiative represent a blend of FDA, NIH, NIST, CDC, diagnostics manufacturers, funding organizations, and payers. Their shared goal is to ensure the accuracy of diagnostic results for oncology patients. However, the lack of standardized, community-validated reference samples and data benchmarks has cast a shadow on the efficient development of crucial tests and comprehension of their results.
The SRS Initiative's journey unfolds in two phases:
Phase 1, initiated in 2018 and now successfully concluded, aimed to address the gap in reference materials for NGS-based diagnostic tests. The fruit of this labor was the MDIC's SRS Landscape Analysis in 2019. This comprehensive catalog documented clinically significant cancer variants and the available reference samples, serving as a stepping stone for the subsequent stages.
Phase 2 is ongoing—the initiative has earmarked 10 variants with direct clinical relevance to cancer. These variants are poised to be integrated into the GM24385 (PGP/GIAB) cell line by Revvity, a manufacturing partner. This step will result in characterized and validated data sets, supported by a collaboration with the NIST. This partnership will verify engineered mutations and craft datasets for ongoing research and regulatory pursuits.
SRS Initiative: A model for reference sample development
The SRS Initiative propels the concept of reference sample development to new heights. Its pilot project is guided by several pivotal objectives: First, the SRS Initiative paves the way for enhanced validation and accuracy of NGS-based diagnostic tests, harnessing characterized and validated somatic reference samples.
Second, the SRS Initiative has the potential to reshape the regulatory review process, potentially streamlining steps and expediting the development of companion diagnostics (CDx) and therapeutics.
Third, the SRS Initiative lays the groundwork for a sustainable model of somatic reference sample and dataset generation, igniting possibilities for broader applications across various cancers and diseases.
Stay tuned for part-two of this blog post, where we'll delve into the multifaceted utility of these reference samples beyond regulatory applications. From diagnostic development to reimbursement, adoption, and disease management, the impact of the MDIC SRS Initiative reverberates through the entire product lifecycle.