Navigating the rapids: the development of regulated next-generation sequencing-based clinical trial assays and companion diagnostics

Abstract

Over the past decade, next-generation sequencing (NGS) technology has experienced meteoric growth in the aspects of platform, technology, and supporting bioinformatics development allowing its widespread and rapid uptake in research settings. More recently, NGS-based genomic data have been exploited to better understand disease development and patient characteristics that influence response to a given therapeutic intervention. Cancer, as a disease characterized by and driven by the tumor genetic landscape, is particularly amenable to NGS-based diagnostic (Dx) approaches. NGS-based technologies are particularly well suited to studying cancer disease development, progression and emergence of resistance, all key factors in the development of next-generation cancer Dxs. Yet, to achieve the promise of NGS-based patient treatment, drug developers will need to overcome a number of operational, technical, regulatory, and strategic challenges. Here, we provide a succinct overview of the state of the clinical NGS field in terms of the available clinically targeted platforms and sequencing technologies. We discuss the various operational and practical aspects of clinical NGS testing that will facilitate or limit the uptake of such assays in routine clinical care. We examine the current strategies for analytical validation and Food and Drug Administration (FDA)-approval of NGS-based assays and ongoing efforts to standardize clinical NGS and build quality control standards for the same. The rapidly evolving companion diagnostic (CDx) landscape for NGS-based assays will be reviewed, highlighting the key areas of concern and suggesting strategies to mitigate risk. The review will conclude with a series of strategic questions that face drug developers and a discussion of the likely future course of NGS-based CDx development efforts.

Keywords: clinical next-generation sequencing; companion diagnostics; disruptive technology; drug development strategy; molecular diagnostics; mutation detection methods; next-generation sequencing; precision medicine.

Figure 1

Schematic representation of the various bioinformatics and statistical analysis steps of a typical clinical NGS variant detection data pipeline. The graphic illustrates the major modules of the pipeline and their output file types, beginning with raw reads (DAT files) and ending with a clinical report. The pipeline is highly tunable, as each of the steps can be optimized by adjusting parameters specific to each step. The triangular shape is intended to convey that each step acts as a filter to remove reads that do not represent variants. The key quality filters that can be applied are shown in the boxes to the right.

Figure 2

Aspects and key considerations of clinical NGS data reporting. Main aspects of clinical data reporting are shown in ovals to the left; key considerations are shown in boxes to the right. The uppermost three aspects rely on the bioinformatic pipeline. What test results are reported in the clinical report (fourth oval) is influenced by socio-ethical considerations and may require genetic counseling and support systems. The evolving payer landscape and medical records guidance will affect how NGS clinical reports are captured in patient records.

Figure 3

Regulatory models for development of NGS-based diagnostics. The FDA device classification for a regulated NGS-based diagnostic device will depend on the perceived risk associated with the diagnostic device.

Figure 4

Coordination of drug and device development for a successful companion diagnostic submission. Drug companies and diagnostic developers may work together in several different cost sharing and assay development landmark payment formats for the development of the final IVD product.