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EU Awards €4.8M to Support Transition of NGS Workflows to Clinical Settings

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CHICAGO – A European Commission project to standardize next-generation sequencing workflows in hopes of making precision medicine a standard of care in oncology has moved into its second phase with the awarding of 11 contracts collectively worth nearly €4.8 million ($5.1 million). Program coordinators did not break out the value of each component.

This program, called Integrated and Standardized NGS Workflows for Personalised Therapy (Instand-NGS4P), is intended to develop workflows for integrating, standardizing, and analyzing data from cancer gene testing, pharmacogenomics testing, and medication databases to support clinical decision support at the bedside.

"Our goal [is] to really cover the complete diagnostic workflow, starting from the sample collection from the patient to isolation of nucleic acids to library preparation, sequencing, bioinformatics, and then up to producing the proper reports for decision-making at the bedside," said Kurt Zatloukal, professor of pathology at Medical University of Graz in Austria.

Instand-NGS4P, a Horizon 2020-funded, 65-month precompetitive program that began in 2020, involves a buyers' coalition of seven hospitals across Central Europe that are already employing NGS for research and diagnostics. The group also includes patient advocacy groups and participants in programs such as the European Life-Sciences Infrastructure for Biological Information (ELIXIR).

Medical University of Graz is the lead center for Instand-NGS4P and Zatloukal is the de facto director of the program. The hospital group also includes the University of Florence and the University of Milano-Bicocca in Italy; Erasmus University Medical Center in the Netherlands; Christian-Albrecht University of Kiel in Germany; St. Anna Children’s Cancer Research Institute in Austria; and Centre Léon Bérard in France.

Zatloukal explained that the EC put out a call for technological innovations to make NGS available to more patients in clinical rather than research settings. The commission "also wanted to see engagement with some of the European reference networks for rare diseases, and they want to see some standardization," Zatloukal added.

Zatloukal confirmed that the consortium of seven hospitals engaged with more than 200 entities, including other healthcare organizations, standards-development organizations, and patient advocacy groups, as the EC encourages, to define unmet needs that the contracts aim to address.

Phase 1 was for proposing designs. The current Phase 2 is the proof-of-concept stage, while the third and final phase will involve implementation and testing of technology in real-world clinical settings.

Alistair Johnson, chief professional services officer at Congenica, which won two contracts in Phase 2, said that the first phase allowed the British bioinformatics firm to think more about what patient-centric and pharmacogenomic reporting should look like and how it should fit in with other Congenica technologies.

He said that adoption of pharmacogenomics historically has been low not only due to lack of funding or reimbursement but also because the information delivered has not met the needs of prescribers. "This program and some of the other work that we have been doing [have] given us an understanding of how to do that," Johnson said.

Phase 2 runs from Nov. 16, 2022, through March 16, 2024, though the contractors must submit their deliverables by the end of 2023 to allow time for evaluation. There will be a midterm evaluation in June, according to Henrik Plym-Forshell, chief commercial officer for healthcare at BC Platforms, one of the contractors.

Zurich, Switzerland-based BC Platforms formed a consortium with Euformatics and Oncompass Medicine to pursue the two contracts they won together. This combined effort is called EU Onco-Platform, drawing from the names of the three companies.

The Graz-led buying coalition will provide feedback to the contractors on usability and on how well the technology can be integrated into routine diagnostic workflows, Zatloukal said.

The 11 new contracts cover what were supposed to have been four "lots": presequencing, sequencing, bioinformatics analysis, and integrated reporting. However, there were no sequencing awards because, according to Zatloukal, the buyers' group received just one application for the sequencing lot in Phase 2, and the European Commission requires at least two proposals for making awards in precompetitive programs.

Horizon 2020 requires that at least half of the R&D activities be performed in Europe, and most of the major sequencing firms are headquartered in the US. Zatloukal said he was "surprised" that UK-based Oxford Nanopore Technologies did not bid for an Instand-NGS4P contract, but noted that the program's tight timelines are more suited for small and medium-size enterprises than larger companies with bureaucratic decision-making processes.

Zatloukal said that the seven hospitals already have sequencing platforms — largely from Illumina and Thermo Fisher Scientific — that are adequate for testing innovations in the other three Instand-NGS4P categories.

According to Johnson, Lot 3, the bioinformatics component, is about "providing information that relates to an appropriate treatment based on the molecular structure of the tumor" in hopes of moving toward targeted therapies and away from chemotherapy and radiotherapy as first-line options.

Lot 3 contains a fairly detailed set of requirements for Instand-NGS4P that Plym-Forshell described as "fairly stretched" compared to what the EU Onco-Platform partners have met before.

While the companies can build on top of existing technology to support the workflows the Graz-led group have called for, "lots of R&D is needed on top of what we already have as commercial products to make this happen," Plym-Forshell said.

Lot 4, which works in concert with Lot 3, deals with the delivery of clinical decision support — pharmacogenomic reports and other recommendations — to the point of care with an eye toward improving patient outcomes. "Although it is not expressly called out in the actual principles of the program, cost effectiveness has to be a part of the thinking as well," Johnson said.

Because informatics and integrated reporting are so intertwined, several of the awardees won contracts in both lots, including BC Platforms, Congenica, and the Centre for Genomic Regulation in Barcelona, Spain.

Under its two contracts, Congenica is building an automated secondary pipeline for variant calling and classification, then an automated reporting application to provide therapeutic guidance at the bedside.

Johnson said that Congenica has been working on the "foundational components" of a single application for precision medicine for some time, and will be offering an early-access program as soon as next month in hopes of a commercial launch by mid-2023.

This technology is meant to make precision medicine more accessible and affordable to smaller hospitals and cancer centers, according to Johnson.

Initially, reports will continue to go to pathologists rather than bedside physicians, in part because that is the current standard of care, but also because the current Congenica technology is not optimized for pharmacogenomics, according to Johnson. Instand-NGS4P is funding some necessary workflow changes to improve how technical genomic data is translated into actionable recommendations for frontline clinicians.

Johnson said that it is paramount that Congenica and other contractors make the analysis and reporting pieces compatible and interoperable in case any of the vendors are not completely successful in their Instand-NGS4P work.

"We have to be mindful of the requirement for interconnectivity to other reporting platforms," Johnson said. "But the principle of what we are building is it's an end-to-end system that does all of those pieces within the same implementation."

The buyers' group committed to co-fund 10 percent of expected development costs, according to Zatloukal, so the hospitals are hoping that the contractors develop technologies they and other hospitals want to purchase in the future. Because the technology will be used in clinical settings, it must comply with the EU's In Vitro Diagnostic Regulation (IVDR).

The contractors expect that their development within the parameters of this program will help them achieve IVDR compliance.

Zatloukal said that in Phase 1, the buyers' group found that there is ever-increasing demand for whole-exome and whole-genome sequencing because gene panels simply are not broad enough when it comes to diagnosing many rare diseases.

Also, he said it is unlikely that technology developers will want to pursue CE IVD marking for technology that only detects rare diseases. "We always need a solution that is open enough, allowing it to also be used as a lab-developed test for rare diseases," Zatloukal said.

The IVDR requires applicants to show clinical evidence for approvals, a difficult task with whole-genome sequences because so many variants are still of unknown significance. "Therefore, we proposed an approach [in which] we generate … virtual panels out of a whole-genome sequence with those variants for which the clinical evidence is sufficiently established," Zatloukal said.

Plym-Forshell said that IVDR "will put more pressure on the hospitals, which in turn likely will turn to the vendors to have preapproved workflows that work together." But gaining that certification will likely open the market for these new products to hospitals that want to buy technology that has been vetted for standards compliance.

Approximately 240 institutions across Europe have "expressed an interest in the outcome" of Instand-NGS4P, and thus represent potential customers, according to Johnson.

He said that the EU program is causing Congenica to look to automate more of its analysis and thus improve usability.

"The overall paradigm of genetic diagnosis is around discovery, so, the foundation stones were around inherited diseases," Johnson said. But the purchasing coalition is looking for information around "known knowns," according to Johnson, so human intervention in the form of curation is less necessary.

"We are applying that to all of our services," Johnson said. "If we think about rare disease diagnostics, for example, we are focusing very much on how we automate that diagnostic process."

Johnson said that Instand-NGS4P represents the "future of genomic medicine … and the future of precision medicine" by producing information in a format that clinicians and patients can understand and use in practice.

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