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First Newborn Sequencing Study Gets FDA Green Light While Others Still Await Approval

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NEW YORK (GenomeWeb) – A study by Children's Mercy Hospital is the first of four newborn genome sequencing projects funded by the National Institutes of Health in 2013 to satisfy requirements by the US Food and Drug Administration, GenomeWeb has learned, after the agency stepped in last year to regulate the four pilot studies.

The study, which started enrolling patients this fall, appears to be the only one of the four that has launched 15 months after the awards were made, which may or may not be related to the FDA's oversight.

This is the first time the FDA has asked research projects funded by the National Human Genome Research Institute to go through an Investigational Device Exemption (IDE) process, according to Anastasia Wise, director of the Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT) program, which is jointly funded by NHGRI and the National Institute of Child Health and Human Development (NICHHD).

IDE regulations apply to certain clinical studies that involve the development of in vitro diagnostic tests. The fact that the FDA decided to submit the newborn sequencing studies to the IDE process appears to be another indication that clinical genomic research is moving quickly into medical practice.

Other genomic research projects will also likely fall under the FDA's purview. For example, as GenomeWeb reported earlier this month, this summer the NHGRI and NICHD, possibly following FDA's lead, stated in a request for applications for the Electronic Medical Records and Genomics Network (eMERGE) that new sequencing methods used in clinical care as part of the research may require an IDE from the FDA.

The four awards under the NHGRI and NICHD's Genomics Sequencing and Newborn Screening Disorders research program were made in September of 2013. The program is funded with a total of $25 million over five years and will explore the potential of genome and exome sequencing to improve healthcare in newborns.

The four funded projects are headed by Robert Green and Alan Beggs at Brigham and Women's Hospital and Boston Children's Hospital; Stephen Kingsmore at Children's Mercy Hospital; Robert Nussbaum at the University of California, San Francicso; and Cynthia Powell and Jonathan Berg at the University of North Carolina at Chapel Hill.

According to Kingsmore, the FDA contacted his group shortly after the awards were made, expressing an interest in its study, which plans to sequence the genomes of critically ill newborns in the neonatal intensive care unit using the rapid STAT-seq assay that the group previously developed. In a prospective randomized study, the researchers are comparing STA-seq to the standard of care in terms of diagnostic rate, time to diagnosis, change in care, impact on morbidity and mortality, and other criteria.

After an initial phone call with the FDA, it became clear that the agency wanted all four projects to go through the IDE process. "They let us know that they thought we probably needed to get an investigational device exemption, and that the process to making that decision was for us to file a pre-IDE," which all four projects did, Kingsmore told GenomeWeb.

The Children's Mercy researchers submitted their pre-IDE application to the FDA's Office of In Vitro Diagnostics in March of 2014, explaining their study and the sequencing technology – the project will use HiSeq sequencing platforms from Illumina – and analysis methods they were going to use to diagnose the infants. "From our standpoint, the actual sequencing device is just one component," Kingsmore said, "so we outlined the entire process to them."

The FDA responded in late April with a number of specific questions, which the researchers addressed in a phone conference in early May. Most of the requests were minor, but one area the FDA was concerned about was the study's plan to disclose certain results from next-gen sequencing to clinicians prior to their confirmation by Sanger sequencing under exceptional circumstances, when they would reveal a life-threatening treatable condition. "It would be verbal, not a written report in the medical record, it would be very rare for us to do that, and we would make sure the clinician understood that it was a provisional result," Kingsmore explained.

Kingsmore and collaborators were able to present the agency with data from 30 families they had analyzed so far, showing that they only disclosed results prior to Sanger sequencing in a single case, which resulted in the survival of the child. In addition, they pointed out that all sequencing was performed in a CLIA-certified and CAP-accredited laboratory.

Within a week, the researchers received a memo from the FDA informing them that they did not require an IDE because the study was determined to be of "non-significant risk." Over the next several months, the study was approved by Children's Mercy's institutional review board and formally launched in early October, a little over a year after the award was made. As of early December, 10 families were enrolled in the study.

While the IDE process might have delayed the start of the study slightly, Kingsmore said it was overall helpful. "It took us a couple of months to prepare the pre-IDE submission because none of us had ever done it before, so we were kind of struggling with what exactly we were going to put into this document," he said. "On balance, I feel that it was very worthwhile. I'm grateful that the FDA took interest and made us do work that we would not otherwise have done − it helped guide our study design."

For example, he said, the FDA's concerns made them think harder about what situations would justify the return of results without confirmation with an established method like Sanger.

Also, the fact that the study protocol had effectively been audited by the FDA might have made it easier to gain IRB approval. "It helped our IRB be comfortable with what we were proposing," Kingsmore said. Going through the IDE process once might also help his team submit future studies to the FDA, he added.

For Kingsmore, the FDA's involvement is a logical development since "at some point, this is research that needs a level of oversight because it's touching patients," he said. "It's not research that's divorced from the clinic. We just happened to be the first project that the FDA has clearly said 'we feel we need to arbitrate over these protocols.'"

For some of the other projects, however, satisfying the FDA's requirements has not been as smooth sailing as for Children's Mercy.

The University of North Carolina's project, for example, was deemed to be a high-risk study by the FDA and will need to submit a full IDE application, which the researchers are currently working on, according to Powell.

"The FDA is interested in all aspects of our study, not just the sequencing," Powell told GenomeWeb. "I think their main concern is that we will be sequencing otherwise healthy newborns and returning results," which will all be confirmed by Sanger or other established technology in a CLIA laboratory. In addition, she said, the agency had concerns about presymptomatic genetic testing in children, which her group is well aware of and addressed, pointing out that families will go through detailed informed consent as part of the research study.

The UNC study plans to enroll families probably in late spring, and had never planned to enroll patients before 2015, Powell said.

The current status of the Brigham and Women's and UCSF studies is unclear. As of earlier this month, Brigham and Women's was still preparing a response to the FDA. Principal investigators from both projects did not provide additional comment before press.

According to NHGRI's Wise, several projects are still in the process of obtaining institutional approval from their local IRBs to begin their work.

NHGRI and NICHD are "working as best they can with our grantees and the FDA as the agency works to apply its regulatory procedures to the new and rapidly evolving area of genomic medicine research consistent with requirements," she said.

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