Article

Expanding next-generation sequencing (NGS) in routine clinical diagnostics

Next-generation sequencing (NGS) has enabled scientists and clinicians to better understand the genetic mechanisms linked to conditions in areas such as women’s health or in diseases like cancer and infectious disease. More importantly, these advances have given rise to improved diagnostics in the clinic for early intervention and monitoring treatment response, ensuring patients get the best therapies possible. Compared to first-generation sequencing and other popular diagnostic methods that are expensive and laborious, NGS has become widely accepted as the best tool for identifying subtle genetic differences in disease.

 

  • The ability to rapidly generate large volumes of NGS sequencing data per run, together with a decrease in sequencing costs, allows for several advantages over traditional, more labor-intensive approaches.
  • Additionally, NGS enables the sequencing of millions of fragments simultaneously per run and the detection of genetic variants for multiple genes in parallel. This is particularly true of short-read sequencing, which is extremely cost-effective and highly accurate for minor variant detection.
  • On the other hand, long-read sequencing can resolve regions of the genome that are inaccessible to short reads, but the costs and error rates in variant detection currently limit its use in routine clinical applications.

 

While there have been significant technological and cost-effective advances in analyzing the genome with NGS, the method has not yet been widely used in routine clinical practice for diagnosis. This suggests that there remain many challenges and uncertainties that clinical laboratories, regulatory agencies, payers and other stakeholders need to address before NGS becomes standard for diagnosing diseases or biomarker testing.

 

The significant barriers to the successful adoption of NGS tests in pathology laboratories are:

 

  1. Establishing and demonstrating both the clinical and economic value of an NGS diagnostic test.
  2. Operating in a frequently evolving regulatory landscape for LDTs and uncertain reimbursement environment.
  3. Implementing complex methodology and demanding protocols.
  4. Managing the abundance of data produced by NGS.
  5. Standardizing bioinformatics analysis for more accessible data interpretation.

 

In addition to the above challenges, diagnostic companies require substantial investment to develop and validate the tests, without guaranteed laboratory adoption. The investment for a diagnostic company developing an IVD test on a Food and Drug Administration (FDA)-cleared platform can be upwards of $20-30M from validation through FDA approval.3

NGS in the clinic
Next-generation sequencing in the clinic

Two types of tests leverage NGS for clinical diagnostics: laboratory developed tests (LDTs) and in-vitro diagnostics (IVDs). A majority of NGS tests are performed using LDTs, which are developed by a single laboratory when an approved diagnostic test is not commercially available. Commercially available IVD assays, however, are more widely used because they are approved or cleared by regulators, utilize a standardized operating procedure that can be followed easily, have high-throughput capabilities and are cost-effective.1

LDTs and IVDs each have their advantages and disadvantages, which directly relate to facilitating their adoption in routine clinical diagnostics. For example, while LDTs are complex and require high levels of expertise for operation, they can be incredibly flexible and modified as innovations are made. On the other hand, IVDs are simple, off-the-shelf tests that any laboratory or organization can perform, but lack the innovative versatility afforded by LDTs.1,2

Adopting LDTs for clinical routine diagnostics requires ease-of-use for laboratories outside of the original lab and quick turnaround to ensure timely decision-making by clinicians. With both IVDs and LDTs, the need for easily-attainable, reproducible, reliable and cost-effective results that lead to robust clinical utility will enable the widespread adoption of NGS technology.

Automating clinical NGS

As the demand for diagnostic NGS testing increases for diseases like rare genetic disorders and cancer, automating NGS steps will be vital for the acceptance and adoption of NGS tests in routine clinical practice. With complex, time-consuming workflows in NGS, automation systems with library preparation for sample analysis will help ensure that results are valid.

A key advantage of automating library prep is that it enables clinical laboratories to produce error-free, reproducible results as well as allowing technicians to devote more time to value-added tasks.3 Using automation for NGS also lets laboratories incorporate multiple disease diagnostic tests onto a single system, significantly expanding the breadth of diagnostic panel offerings to clinicians and patients.

Automating NGS
Regulatory and reimbursement challenges

Each country has its regulatory agencies that govern the approval or clearance of clinical diagnostics. Reimbursement from public or private payers is also vital for successfully implementing NGS into routine clinical practice. To this end, lab directors can act as crucial components for educating regulatory agencies and payers on the importance and validity of NGS routine clinical diagnostic testing.

For both payers and regulators, LDTs and diagnostic testing solutions need to be standardized and provide reproducible and accurate results, similar to that of IVDs, and demonstrate clinical validity.4,5 These tests should inform clinical decisions and accurately identify clinical status to help ensure that they are approved and covered.

Roche’s commitment to NGS clinical diagnostics

As the demand for routine clinical diagnostics, such as cancer panel testing and non-invasive prenatal testing increases, Roche continues to be committed to leveraging its expertise and innovation to create future high-throughput, cost-effective, automated NGS diagnostic and screening solutions to clinical laboratories to increase efficiency and reduce costs.

By working closely with all stakeholders, including clinicians, payors, and regulatory authorities, Roche has the goal of providing patients with routine diagnostics through its NGS product portfolio to ensure future patients are screened and monitored to receive the best care possible.

References

 
  1. Genzen J. Am J Clin Pathol. 2019 Jul 5;152(2):122-131.
  2. Mamuszka H. J Precision Med. 2019 June.
  3. Hess JF. et al. Biotechnol Adv. Jul-Aug 2020;41:107537.
  4. Deverka P. et al. JAMA. 2014 Nov 12; 312(18): 1857–1858.
  5. Wise J. et al. Drug Discov Today. 2019 Nov;24(11):2120-2125.