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FDA, Labs, Vendors Take Steps Toward Regulatory Ground Rules for Array-Based Cytogenetic Testing

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This story was originally published on July 2.

By Justin Petrone

BETHESDA, Md. — Hoping to plug an "unregulated hole" in its oversight of medical devices, the US Food and Drug Administration last week hosted a public meeting to address the use of array-based tests in diagnosing genetic abnormalities.

The meeting included presentations from the FDA, representatives of labs that offer array-based cytogenetic testing, and other experts. Though present, array vendors did not contribute to the panel discussion during the meeting.

While FDA representatives made it clear that the agency will in the future require array manufacturers to seek clearance in order to sell their chips for use in clinical cytogenetics, it has not yet reached a decision on what criteria it expects vendors to fulfill in order to achieve such clearance.

Alberto Gutierrez, director of the FDA's Office of In Vitro Diagnostic Device Evaluation and Safety, noted that due to the challenging nature of regulating these tests, which have become widely adopted by cytogeneticists over the past five years, they have "fallen into an unregulated hole to some extent." The FDA is working with array vendors to establish "what is rational, reasonable, and how can we go about setting rules for the road for this space," he said.

"We have been struggling with validation challenges for these assays for some time," said Donna Roscoe, a scientific reviewer in the division of immunology and hematology at the FDA's Center for Devices and Radiological Health. She acknowledged that array-based cytogenetic tests, which look across a patient's genome to identify causes of certain phenotypes, "challenged FDA's regulation strategy" because they provide an "undefined number of outputs open to interpretation."

Because of this, FDA is now looking to create "standards for manufacturers seeking to bring assays for approval," and to ensure that array-based cytogenetic tests are "safe and effective," Roscoe said.

The question of how to evaluate and ultimately clear array-based cytogenetic tests, though, remains unanswered. Some argued that the capability of cyto labs to discover, for example, new, rare syndromes using the technology will make it difficult for the FDA to permit the use of whole-genome arrays in cytogenetics.

"The FDA has done a wonderful job over the years in evaluating and approving various genetic tests of single mutations, but that model was also invented because before a certain date there was no genetic testing," said Bassem Bejjani, co-founder and chief medical officer of Spokane, Wash.-based genetic testing lab Signature Genomics, which is now part of PerkinElmer. "Now at the threshold of a new era, we should be creative and see if some other model might fit."

Rather than look at what content is on the chips that are used in cytogenetic services, Bejjani recommended that the FDA instead clear microarray platforms submitted by vendors on the technologies' ability to accurately measure copy number variation. "Instead of looking at group of CNVs related to specific syndromes, look at arrays as CNV measuring tools," he said.

"Manufacturers need to document that they measure SNPs and CNVs accurately," said Arthur Beaudet, chair of the department of molecular and human genetics at Baylor College of Medicine. "They don't need to document anything about clinical utility."

At the meeting, Beaudet likened arrays to magnetic resonance imaging machines, and argued that the clinical interpretation of data generated by arrays falls within the practice of medicine and, thus, outsidethe FDA's regulatory purview.

Calling the use of chromosomal arrays the "most significant clinical benefit that has come out of the Human Genome Project," Beaudet cautioned against forcing manufacturers through a clearance process that will limit the use of the technology, though he acknowledged that the current framework, where arrays are still offered as laboratory-developed tests, was unlikely to survive.

"Do we need more governmental regulation of deep-sea drilling or of genetic testing? I think we'll have more of both whether we like it or not," said Beaudet. To guide the FDA forward, he offered a two-part approach to regulating the area based on the analogy to clinical imaging, leaving the FDA to regulate the technology, but leaving it up to board-certified practitioners — the radiologists of the genomics world or, in Beaduet's words, the "genomicists" — to interpret the data.

"Does the FDA require manufacturers of MRI machines to provide sensitivity, specificity, and clinical utility for foreign bodies of every conceivable size and composition?" asked Beaudet. Going forward, he predicted that "either the great majority of genetic testing" will not be FDA approved, or the FDA could "shut down the latest and greatest technology."

Michael Watson, executive director of the American College of Medical Genetics, agreed that those performing the interpretation of array results be licensed to do so. "Those performing and interpreting results should be certified genetics professionals as defined by ACMG standards," Watson said. "The FDA could require special controls for professionals, and confirmation of an alternative technology could be required," he suggested.

The FDA seemed receptive to the idea that the agency would in the future regulate platforms rather than the labs that provide the interpretation. Still, FDA representatives declined to commit to a framework for regulating the space, stressing they were in the process of formulating such an approach.

"I wouldn't say MRIs are entirely analogous [with arrays], but we get your point," said Elizabeth Mansfield, director of personalized medicine staff at OIVD." She said the agency "may not see a need for analytical specificity" in its future review process, but that the FDA is taking into account the considerations of labs and vendors and is "unlikely to publish a special guidance or control document prior to discussions with vendors" about clearance.

"We think this is a wonderful area of medicine and we would certainly like to add to that rather than to block it," said Mansfield.

How to Do It

Sherri Bale, president and clinical director of Gaithersburg, Md.-based genetic testing firm GeneDx, made several recommendations during the meeting about how best to regulate the use of arrays in cytogenetic testing.

"Most labs now use oligo-based arrays manufactured with a high degree of computerized control and no human intervention in the process," said Bale, "so the production of arrays should be straightforward; what you put in is what comes out."

Bale believes that array manufacturers should provide certificates that attest that the appropriate quality-control assessments were carried out. Once an array comes to a testing lab, Bale recommended that it be evaluated with DNA samples from individuals with known abnormalities. She also said the FDA might wish to make recommendations on what content is on the arrays, even if the chips used by various labs might include more content than is recommended.

While labs seemed receptive to the idea of content recommendations, participants were opposed to the idea that they be obligated to adopt a cleared, consensus-designed array into their services.

"If you go with a consensus design, you go with the least cutting-edge array," said Beaudet. "It could be good, and 90 percent of field could use it, but there should be freedom to move the field forward with custom designs," he said. "Some flexibility should be available."

Brynn Levy, director of the clinical cytogenetics laboratory at Columbia University Medical Center, agreed that "if you go through the FDA process and imprint a design, it will be obsolete the moment it comes out."
Levy said that "manufacturers should guarantee that when you see something above [a certain] threshold, what you see is what you get."

David Ledbetter, director of the division of medical genetics at the Emory University School of Medicine and the head of the International Standard Cytogenomic Array Consortium, similarly noted that consensus designs also continue to evolve, as the ISCA's consensus array design has shown.

"Consensus design is not a stagnant [process,] but a dynamic process, relying on community input, evidence-based reviews, and updates confirmed with the tolerance of users and regulatory considerations," Ledbetter said. "Whether the frequency of updates is every six months or every year, you have to have a dynamic process in place to update your arrays."

Because of these frequent updates, some panelists at the meeting suggested that the FDA may be forced down the road of assessing the technological performance of arrays, versus the content on those arrays, as platforms are less of a moving target for regulation.

"We need to separate analytical validation from clinical validation," said Timothy O'Leary, director of clinical science R&D and biomedical R&D services at the US Department of Veterans Affairs. "The FDA needs to focus on the analytical validation of things, as it will be the only thing that will be sufficiently static as arrays go from being commonplace to commodity."

While labs have been free to offer their tests as LDTs in Clinical Laboratory Improvement Acts-compliant facilities in the US, New York State continues to insist on a separate clearance process for local labs.

According to Ann Willey, director of the Office of Laboratory Policy and Planning in New York's Department of Health, since the advent of array-based cytogenetic testing, the state has struggled to regulate these services through its existing framework for LDTs.

For a New York lab to offer the tests the applicant must provide data that shows it can perform the assay and the state requires that all abnormal results be confirmed by an independently validated assay, such as fluorescence in situ hybridization, she said.

Still, Willey noted that the field is "evolving very rapidly" and said that every time a lab changes its design, it must submit documentation on the new design. "For labs to keep up with submissions and for us to keep up with reviews is extremely problematic," said Willey. "We would like to see the FDA work with vendors so that we don't need to do this anymore."

'A Messy World'

One issue raised at the meeting was how to manage the existence of so-called "incidental findings" —gains or losses detected with array technology that so far cannot be explained to patients. While labs that offer these services aim to determine the genetic causes of abnormalities, in some cases they encounter variants that can neither be defined as benign nor pathogenic.

As the Department of Veteran Affairs' O'Leary noted, it would be "almost impossible" for the FDA to construct a regulatory framework around these tests that "takes into account heterogeneity of diseases and heterogeneity of the people" who interpret the findings. "It's a messy world out there," he said.

Signature's Bejjani pointed out that such incidental findings are "not new in medicine or genetics. " It is "not uncommon for a radiologist to make a diagnosis of pneumonia in a patient with abdominal pain," Bejjani said. "In a chromosome analysis on a patient with suspected Down syndrome, it is not uncommon to identify another unrelated abnormality," he said. "Reporting of these results should not be restricted but determined by appropriately trained professionals."

Emory's Ledbetter noted that "95 percent of results" obtained using arrays are "unambiguous," and said "it's the five percent where there are some question marks." He noted that the 95 percent of clear findings were "double or triple yield of existing technologies" in classical cytogenetics.

Bejjani agreed that in "all but 5 percent of cases, you can make a call."

Columbia's Levy warned against restricting the use of arrays to detect only known syndromes in order to mask the regulatory questions raised by incidental findings. "If we restrict analysis to known syndromes, we miss out on other relevant regions that many not necessarily have a designated syndrome but [are] chromosomally abnormal," said Levy.

"Licensed professionals should do the interpretation," he said. "Each lab needs a documented protocol for interpretation of results that conforms to currently accepted standard."

OIVD's Mansfield said that she did not believe the agency could regulate the interpretation of array results, but may in the future increase its oversight over who could make those interpretations.

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