Alex Philippidis Senior News Editor Genetic Engineering & Biotechnology News

CtDNA Tests Attract Interest from Companies, Institutions, and Regulators

Dazzled by the prospect of a market projected to reach $22 billion by 2020 (BCC Research), several companies and institutions have either introduced circulating tumor DNA (ctDNA) tests to market or plan to do so.

Yet when Pathway Genomics launched its CancerIntercept Detect™ test last September for $299 to $699, the company incurred the wrath of the FDA. In a September 21, 2015, letter to Pathway Founder and CEO Jim Plante, the agency said the early-detection test “appears to meet the definition of a device” because it includes blood-collection tubes. The FDA also questioned whether a white paper posted on Pathway’s website adequately supported its claim that the test could effectively detect cancer in undiagnosed patients for up to 10 different cancers.

“We believe you are offering a high risk test that has not received adequate clinical validation and may harm the public health,” wrote James L. Woods, deputy director, patient safety and product quality at FDA’s Office of In Vitro Diagnostics and Radiological Health.

Pathway countered with a statement concluding: “We believe we have performed appropriate validation of the test as a laboratory developed test, and we are in the process of performing additional studies.”

Pathway has two clinical studies underway on CancerIntercept Detect, both launched after the FDA letter. One study will test 1000 or more individuals for the presence of 96 ctDNA mutations in nine cancer driver genes. The other will assess an estimated 200 patients without known cancer who are scheduled to undergo a screening or diagnostic colonoscopy to see if the ctDNA test can detect a cancer or precancerous condition before symptoms are seen.

Plante told GEN on February 25 the company has also initiated three clinical studies involving CancerIntercept™ Monitor, a blood-based tumor profiling test designed as a noninvasive, less expensive adjunct to traditional biopsy methods.

“These studies will involve patients undergoing screening for Li-Fraumeni syndrome, lung and thyroid cancers,” Plante said. “Our dialogue is still ongoing. We met with the FDA and submitted a response. We are hopeful to reach a conclusion in the near future.”

Pathway declined to disclose what it told the agency, which referred questions on the response to the company.

Getting the Answers

The FDA insists it is not looking to derail ctDNA or stop development of new technologies.

“We don’t want to stifle people having access to their genetic information. We think that that’s very important,” an FDA spokesman, Eric Pahon, told GEN on February 23. “But we feel it’s also critical that we make sure people are getting the answers that they think they’re getting, that these tests are safe and effective, and they’re not going to hurt anybody.”

The FDA’s scrutiny of Pathway’s test comes as the agency prepares to issue final guidance intended to regulate “high-risk” lab-developed tests (LDTs) along the lines of Class III medical devices. While the FDA’s draft guidances are friendlier to for-profit diagnostic developers than nonprofit academic medical centers, both have voiced objections and made counterproposals to the agency.

“If you can get a test on the market and start making some money with it, without having to spend the time and money for FDA to evaluate this test, then I see how that could be very attractive for companies. But that’s also the exact reason why we think it’s so important to closer-regulate LDTs,” Pahon said.

The divide between FDA and Pathway Genomics resembles the one that arose in 2013, when the FDA ordered 23andMe to stop selling its Saliva Collection Kit and Personal Genome Service® (PGS), and submit to agency review of its tests as a medical device.

23andMe began discussions with the FDA and toned down its initial public criticism of the agency. The dialogue reaped results last year when 23andMe won its first FDA authorization for a Bloom syndrome carrier status test indicated for detecting the BLMAsh variant in the BLM gene, based on saliva collected using the FDA-cleared Oragene DX model OGD-500.001.

Unlike 23andMe, Pathway has long been in the agency’s crosshairs. Back in 2010, the FDA derailed the company’s plans to sell direct-to-consumer saliva kits through Walgreens stores by telling Pathway that the tests required 510(k) marketing clearance. The company later said the FDA registered the kits as a Class I device.

Surmounting Two Hurdles

Regulatory scrutiny is one of two key hurdles that ctDNA testing will need to surmount. The other is addressing numerous unanswered questions raised by development of the technology.

The first question is whether ctDNA tests end up detecting cancer in people who are asymptomatic and will not eventually develop cancer? That poses the risks of unnecessary treatment of cancers that aren’t particularly dangerous, cancers that may eventually be cleared up by patients’ immune systems, Harry Glorikian, senior executive, board director, and consultant in the life sciences/healthcare industry, told GEN.

“Determining a threshold at which an intervention will be needed will be even trickier,” Glorikian said. “Will it be sensitive enough to detect the proverbial needle in the haystack, and specific enough to rule out cancer accurately? Early treatment is surgery and radiation and those are tissue specific. It may not be enough to just know the pathway. Will it show the tissue of origin? Will that be the primary tumor site or a metastasis?”

Glorikian added that other challenges to consider—and more importantly to validate through large prospective trials—include standards for isolating DNA, including depth of coverage, biomarker selection, reproducibility of results, and clinical impact of variants of unknown significance.

“ctDNA is highly variable by tumor burden, stage, cellular turnover, accessibility to circulation factors affecting blood volume. High sensitivity is critical,” he said.

How quickly and completely test developers address these issues is likely to determine how quickly and completely payers reimburse healthcare providers for the tests, Divyaa Ravishankar, transformational health senior industry analyst with Frost & Sullivan, told GEN.

For ctDNA tests, as with circulating tumor cells (CTCs), “the three prominent issues/bottlenecks in decreasing order are clinical evidence: evidence for utility of mutations, sensitivity of current technologies to detect ctDNAs, and tedious workflow's of today's technologies,” Ravishankar  said. “Addressing the three would lead to addressing questions surrounding the reimbursement.”

Discoveries Spur Developers

DNA was identified in human blood as early as 1948 and in cancer patients in 1977. In 2013, Dennis Lo, M.D., Ph.D., at the Chinese University of Hong Kong, developed a noninvasive test for cancer by detection of genome-wide hypomethylation of cell-free DNA from patient plasma.

Dr. Lo’s test emerged a year after researchers led by Alberto Bardelli, Ph.D., at the Institute for Cancer Research and Treatment in Turin, Italy, detected KRAS mutations in the tumor DNA of patients whose tumors had become resistant to epidermal growth factor receptor inhibitors, some 10 months before verification through a radiological scan. In 2014, investigators at Johns Hopkins Kimmel Cancer Center found that some DNA fragments shed into the bloodstream by tumors can potentially be used to screen noninvasively for early-stage cancers, monitor treatment responses, and help explain why some cancers are resistant to therapies.

A Johns Hopkins spinoff, Personal Genome Diagnostics (PGDx), has developed an oncology screening platform that includes whole-genome sequencing, pan-cancer panels, targeted panels, and single-gene analysis in tissue and liquid biopsies, as well as custom approaches for target discovery and companion diagnostics. The company raised $21.4 million in series A financing in October, led by New Enterprise Associates (NEA).

Developers committed to developing ctDNA tests for cancer include Boreal Genomics, whose OnTarget™ mutation-detection platform analyzes cell-free DNA in plasma; Trovagene, whose technology isolates ctDNA in urine; and Natera, whose technology is being used by University College London Cancer Institute to detect ctDNA variations in the 840-patient Tracking Cancer Evolution through Therapy (TRACERx) study, focused on how lung cancers mutate, adapt, and become resistant to treatments.

Another startup, Guardant Health, announced its first closing January 7 on most of $100 million in series D financing, led by OrbiMed Advisors. Guardant said the financing would help it enhance its Guardant360® next-generation sequencing-based liquid biopsy test, a 70-gene blood test used in advanced cancer patients with visceral solid tumor cancers or metastases, and expand its Digital Sequencing™ platform into new product lines.

Illumina staked a presence in ctDNA testing in January by launching a new company called GRAIL with more than $100 million raised from investors that include Jeff Bezos and Bill Gates. GRAIL is developing a simple blood test designed to screen for the most frequent types of early-stage cancers.

GRAIL spokeswoman Carolyn Wang told GEN the company’s current thinking is to start clinical trials in 2017. “Given the recent discussion from the FDA about regulating LDTs, we will await their updated guidelines, most likely in the first half of 2016, and move forward with the most suitable strategy for GRAIL.”

Moving forward will mean initiating discussions with FDA to discuss a regulatory pathway for its eventual test, Wang said.

In addition to what tests warrant FDA scrutiny and on what levels, that regulatory pathway should include clear standards on what claims test developers can make and what standards of verification the agency will accept to ensure that tests actually meet those standards.


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