Framing the Challenges of Next-Generation Sequencing

Bioinformatics research has developed rapid, increasingly specific, and cost-effective tools to analyze and interpret health information.

Next-generation sequencing (NGS) is one such tool. Also called massively parallel or deep sequencing, NGS is an advanced technique that can sequence the entire genome in a day, a tremendous leap forward from the Sanger technique, which took over a decade to do so.¹

Applications of NGS

Need for Whole-Genome Sequencing

NGS can include exhaustive parallel sequencing of individual small nucleotide fragments, with the follow-up analysis requiring bioinformatics to reconnect the puzzle based on the reference human genome. The technology has the flexibility to sequence the entire genome or specific areas of interest, such as the whole-exome (22,000 genes) or individual genes.¹Sequencing panels such as OncoType DX, MammaPrint, and Prolaris have had a tremendous impact on clinical diagnosis, prognosis, and treatment decisions in oncology. NGS gene sequencing panels have also found their place in the National Comprehensive Cancer Network guidelines for patients with ovarian cancer.²While whole-exome (the exome is the coding region of the genome) is currently the most popular method of sequencing, there is still a need for whole-genome sequencing funneled by the knowledge that the noncoding regions (introns) of the genome may have direct tumorigenic effects and can cause genomic instability. Individualized whole-genome sequencing offers the potential for personalized treatment and care management.¹

Cost of Sequencing the Human Genome

Identifying specific mutations, developing drugs to target those mutations, and individualizing treatment can improve outcomes and simultaneously reduce some of the side effects associated with the use of cancer drugs.The sequencing of the first human genome, concluded in 2003, required 13 years and cost a staggering $3 billion.³ The picture is very different today: Illumina boasts that the cost of sequencing a single genome is around $1000 and requires just days. These advances create an entirely new spectrum of opportunities to exploit.

Challenges With NGS

Technical

The cost-efficiency boast has a caveat, though: the low price is applicable only for high-volume users that handle huge DNA databases, such as the Broad Institute and the Sanger Institute. Additionally, the up-front cost of the instruments is high, ranging from $50,000 to $750,000.³While scientists surmounted the entire gamut of technical challenges as NGS was being developed, several aspects of the technology remain disputed. These challenges include:

• Data storage. Storage, in a compressed format, of the data generated by a single exome sequencing requires about 10 GB of disk space; at just 3 runs a month, that adds up to 1.4 TB of data. Data analysis requires additional disk space.
• Statistical significance. Achieving statistical significance for the data may be challenging, with respect to finding as many samples to analyze and the associated cost. Collaboration may be key.
• Data safety/privacy. Patient data may be difficult to keep secret. Safety of patients’ genetic information is a prime public concern— information from SNP arrays, exome, or whole-genome sequencing could find its way into wrong hands and be exploited.
• Finding samples. Inter-institutional collaborations may assist with obtaining large numbers of good quality samples. High standards are required to be maintained for sequencing samples obtained by using public funds.
• Functional validation. Genetic information by itself is difficult to sell or make a persuasive argument with, and requires credible support from phenotypic or functional data.
• Translation to the clinic. While several sequencing panels are already being used in the clinic, exome/whole-genome sequencing panels may not be far behind— if challenges with Clinical Laboratory Improvement Amendments (CLIA) certification are overcome.⁴

Reimbursement

Assuming that technical hurdles will be met, how will manufacturers and users ensure that NGS will be reimbursed by payers? Similar to the challenges faced by existing diagnostic panels, analytical validity and clinical utility will top the list of concerns that payers would have with NGS, particularly whole-genome sequencing. Another important concern will be whether the results from an NGS test are clinically actionable to necessitate medical intervention.

The lack of coordinated data generation—based on regulator and payer requirements—has created a difficult-to-cross chasm in the healthcare world. Payers use clinical utility (the impact of diagnostic tests on patient health outcomes) as the gold standard when making coverage decisions. What payers hope to learn prior to making these decisions is whether the test is safe for patients, whether it reliably provides the information needed for clinical decision making, and whether it would add to the rising cost of healthcare.⁵

With the movement toward value-based payment, the other important question that needs to be answered is whether payment for NGS will be based on current reimbursement practices, or a new value-based paradigm will be established, the premise for which would be improved outcomes or reduced spending that results from using the test. While data from diagnostic tests focused on specific disease-associated genes might be relatively easy to analyze and interpret, a broad genomic interrogation by NGS might be complex and would likely require a team of professionals to interpret the results. This would prompt additional questions regarding what is being “valued” when making coverage decisions.⁵

Additionally, most NGS-based tests are laboratory developed tests, or LDTs, and fall under CLIA regulations, not those of the FDA. This raises payer as well as provider concerns about the regulatory oversight of these tests, as was indicated by participants in a panel discussion convened by The American Journal of Managed Care earlier this year.⁶ Panel participant Daniel F. Hayes, MD, clinical director, Breast Oncology Program, University of Michigan Comprehensive Cancer Center, and president-elect of the American Society of Clinical Oncology said: “We critically need to take three actions: modify the regulatory environment, discuss the analytical validity of a diagnostic test, and identify who really decides the utility of LDTs.”⁶

Surabhi Dangi-Garimella, PhD, is the managing editor of the American Journal of Managed Care, Evidence-Based Oncology. Read more at AJMC.

References

1. Behjati S, Tarpey PS. What is next generation sequencing? Arch Dis Child Educ Pract Ed. 2013;98:236-238.
2. Shen T, Pajaro-Van de Stadt SH, Yeat NC, Lin JC-H. Clinical applications of next generation sequencing in cancer: from panels, to exomes, to genomes. Front Genet. 2015;6:215. doi:10.3389/ fgene.2015.00215.
3. Thayer AM. Next-gen sequencing is a numbers game. Chem Eng News. 2014;92(33):11-15.
4. Koboldt D. New challenges of next-gen sequencing. MassGenomics website. http://massgenomics.org/2014/07/new-ngs-challenges. html. Accessed July 7, 2015.
5. Deverka PA, Dreyfus JC. Clinical integration of next generation sequencing: coverage and reimbursement challenges. J Law Med Ethics. 2014;42(suppl 1):22-24.
6. Dangi-Garimella S. The challenges with ensuring the validity and utility of diagnostic tests. Am J Manag Care. 2015;21(SP6):SP173-SP174.