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Diagnostics In DC: FDA Guidances, NGS Assays And Clinical Workflows At The Next Generation Diagnostics Summit

By Allison Proffitt

September 9, 2016 | Diagnostics is exploding thanks to next generation technologies. Advances in NGS assays, point-of-care diagnostics, companion diagnostics, DNA forensics, struggles with interpretation and incidental findings, and the regulatory structure surrounding all of it were the topics of three days of conversations in late August at the Next Generation Diagnostics Summit* in Washington, D.C.

Elizabeth Mansfield, director of personalized medicine for the office of in vitro diagnostics and radiological health at FDA, gave the plenary keynote talk to a packed room of professionals seeking insight into FDA’s plan and view of diagnostic technologies.

Mansfield outlined two FDA draft guidances released in late July on the emerging role of next generation sequencing (NGS)-based in vitro diagnostics (IVDs). The guidances are intended to encourage innovation, promote adoption of good NGS tests, and establish an “efficient path to market”, she said.

FDA’s bar is “safety and effectiveness”, and the Agency seeks scientifically sound evidence proving tests’ analytical and clinical validity.

The Agency’s hope is to define unique regulatory pathways for NGS-based tests, Mansfield said, but “What we really want with these guidances is for a standards group to turn them into standards.”

Mansfield admitted that the FDA can be “kind of slow and intense”, and she sees an opportunity for standards bodies to accelerate the process. Standards for NGS-based tests must be informed by the test’s intended use and indication, Mansfield said.

When FDA first began putting together the draft guidance, the Agency consulted technology providers. It was important, Mansfield said, for the Agency to understand the limits of the technology before involving test developers or clinical labs.

And it was impressed with what it found. While confirming findings with Sanger sequencing used to be standard, “more and more” FDA is comfortable skipping that step, Mansfield said.

With the technical limits in mind, FDA is looking for accuracy, precision, limits of detection, and analytical specificity. We worry about pseudogenes and cross-contamination issues, Mansfield said. The Agency has set minimum performance thresholds of 99.9% accuracy and 95% precision.

The second recently-released guidance outlines how FDA plans to recognize public variant databases. FDA believes that all of science should be moving toward public databases, Mansfield said. 

Easy Adoption

From there, conference content was expansive. Many of the conversations turned to lowering the barrier of entry for new technologies.

Steve Steinhubl, director of digital medicine at Scripps Translational Science Institute, delved into how wearables can help collect data and improve patient outcomes. Healthcare must move away from considering the “quantified” patient. As a cardiologist, Steinhubl said, he is far more concerned about his patients who hate the quantified self movement. Steinhubl believes that wearables are the future of healthcare, but encouraged medical professionals to acknowledge that data have emotional weight. Recognizing that is crucial to patient care. For example, glucose monitors are arguably the oldest self-monitoring devices. There’s a link between asking patients to monitor their glucose levels daily and depression, Steinhubl said. Patients don’t like being frequently reminded of their illness. “How can we design wearables that give people actionable information when it’s convenient?” Steinhubl asked.

The same can be asked of doctors.

“We need to think about operational hurdles for doctors,” said Charles Matthews, VP Boston Healthcare, during a plenary panel. Kimothy Smith, chief technology advisor at PisitiveID, agreed, with a bit more cheek. A tremendous amount of care and thought must go into designing molecular diagnostics that “even a physician can use”, he said.

The Interpretation Question

As always, the interpretation problem was front and center.

Dan Snyder, president and CEO of MolecularMD, agreed that diagnostic tests must be useful and easy for doctors to implement. Many tests are precise, Snyder noted, but the results are still presented to physicians who must decide about clinical validity.

“Results” are just the start, agreed Rebecca McClure, senior scientist, pathology, Health Sciences North. A test may have one result, but several levels of interpretation, she said. We can’t leave that to the databases.

Interpretation, of course, depends on how clinically useful and valid we believe our data to be.

Ted Schutzbank, technical director of specialized testing and microbiology at St. John Providence Health System, referred to an article published this month in The Journal of Molecular Diagnostics teasing apart clinical utility and clinical validity (DOI: 10.1016/j.jmoldx.2016.05.007).

“Definitions consistent with a patient-centered approach emphasize and recognize that a clinical test result's utility depends on the context in which it is used,” the study authors write.

The additional challenge, of course, is that our understanding of variants and the utility of molecular diagnostic tests is constantly changing.

Isaac Kohane, chair of the Boston Children’s Hospital Informatics Program and Co-Director of the Center for Biomedical Informatics, warned the audience against genetic reductionism, the view that your genes are your destiny. 

It’s a temptation to which many of us succumb, Kohane said. “There will be hundreds of “Mendelian diseases” that are going to look like common variants with small effects” once we have more information, he said.

Kohane is not anti-genomics at all—he’s the co-organizer of Boston Children’s Hospital’s CLARITY Challenge to find molecular diagnoses for undiagnosed diseases—but he warned against expecting all of our health issues to be explained by the genetics, when in fact we are ignoring phenotype and even health system dynamics.

For years, Kohane has been exploring how to better mine the data in electronic health records and better understand health system dynamics. (See his 2013 paper, DOI: 10.1371/journal.pone.0064933). “Understanding clinical context is hugely important,” he said.

Precision and accuracy is mostly in non ‘omics data right now, Kohane said. To truly deliver precision medicine, we will need full “clinico-societal-environmental context” for patients.

Until we do arrive at precision genomics, we are left with what Kohane and colleagues termed the Incidentalome (DOI: doi:10.1001/jama.296.2.212). Wayne Grody, a professor of medical genetics and molecular pathology at the UCLA School of Medicine, has been at the heart of the incidental findings conversation. Grody served as president of the American College of Medical Geneticists in March 2013 when the ACMG released its recommendations on reporting incidental findings in clinical exome and genome sequencing. But Grody and the ACMG acknowledged how complex the issue is.

In 2014, his lab at UCLA developed its own clinical NGS workflow (see, DOI: 10.1001/jama.2014.14604). Even in light of the ACMG suggestions, Grody’s group at UCLA continued to offer opt out options for patients.

“I’m not sure we’ll ever fully agree on what to do with incidental findings,” Grody said at the Summit. “In medicine, above all we want to do no harm.”

He recounted a devastating case in which consanguineous parents of a sick baby requested incidental findings. The baby had Batten disease, for which there is no cure. Both parents had variants for early onset familial Alzheimer’s disease.

"I wish we hadn’t found the incidental findings; I wish we hadn’t had to return them. I wish we’d just done a Batten disease test," Grody said.

Three years later, Grody is as aware of the challenges as ever. He was particularly disparaging of wellness screening, calling it “inherently narcissistic”. “What would we even report?” Grody asked, we might get an incidental finding from the ACMG list 2% of the time, and the other 98% are false negatives, he said. The individual isn’t really well. “We’ve only ruled out the few things we know.”

* The Next Generation Diagnostics Summit, Washington, D.C., August 23-26, 2016. The Summit is organized by Cambridge Healthtech Institute, the parent company of Diagnostics World News