CEO SUMMARY: In recent weeks, a client notified Invitae of discordant results on a patient. The notification caused the genetic testing company to discover it had a systemic error that failed to test for a specific rare mutation associated with inherited cancer. Company officials believe only 2 to 15 patients received a false negative test result due to this error, yet because the error went undetected for 11 months, the company will retest 50,000 patients.
ONE OF THE NATION’S LARGER GENETIC TESTING COMPANIES is dealing with a significant problem that may have long-term consequences for how genetic testing labs are regulated at the federal and state level.
Last week, THE DARK REPORT was first to break the news that Invitae Corporation reported inaccurate genetic test results for what it said could be is as many as 50,000 patients over 11 months, starting in September 2016 and ending in July 2017.
The company admitted it failed to test for a specific rare mutation associated with hereditary cancer. In recent weeks, Invitae became aware of the problem and began contacting clinicians to notify them of the error in the genetic test results it reported for certain patients and to arrange to retest those patients. Invitae would not say exactly when it discovered the problem beyond saying, “in recent weeks.”
In a statement to THE DARK REPORT, Invitae said, “For the past several weeks, Invitae has been working with clinicians to address an issue related to our analysis of a rare genetic variant in the MSH2 gene associated with Lynch syndrome (0.007% of inherited cancer tests), also known as the Boland inversion, which we believe could have led to a false negative report for a small number of patients (estimated 2-15 patients impacted).
“Because of the unique characteristics of how we were testing for the MSH2 Boland inversion, our quality control checks did not catch omission of the components of the assay,” the statement continued. “As soon as the omission was recognized and relevant components returned to the assay, it once again performed properly. We have added two separate quality controls to ensure this issue will not reoccur.”
For two reasons, this failure may have significant repercussions—not just for genetic testing companies, but also for the entire clinical laboratory industry. First, Invitae determined that the genetic tests for 50,000 patients were subject to this systemic testing error, a number that is likely a record high for such an error. Second, these assays are laboratory-developed tests (LDTs), which the FDA said in 2014 should be subject to regulation.
Additional factors that make this a significant event for the clinical laboratory profession include the following. Pathologists who are medical directors of genetic laboratories will recognize how these events demonstrate vulnerabilities that exist in their own labs. This episode also highlights the limitations of the current state of technologies and systems used in genetic testing.
In its statements to THE DARK REPORT and in interviews with reporter Turna Ray at Genomeweb.com, Invitae acknowledged the following:
- When it developed a new assay version in 2016, Invitae did not recognize that the probes for the Boland inversion mutation were not included.
- This error occurred in September 2016 and from that time, in normal daily testing operations, Invitae’s internal quality controls did not detect this problem.
- In July 2017, 11 months after it launched the new assay, a clinician notified Invitae of discordant results on a patient who had been tested twice, once by Invitae and once by another genetic testing lab company.
- After being alerted to the discordant results, Invitae confirmed the systemic error and began notifying clinicians of the error and arranging retesting for those patients.
- Invitae said it will retest 50,000 patients and it has notified the College of American Pathologists, its CLIA accreditor, of the genetic testing error.
Story has Two Dimensions
This story will unfold in two dimensions: among investors and among clinicians. Clinicians include physicians and genetic counselors who use genetic tests, and pathologists and laboratory scientists who perform genetic tests.
News reports and financial analyst commentary will die down quickly after investors decide this episode won’t affect Invitae’s ability to pursue its growth plans. In this dimension, the problem at Invitae will be deemed as not material to the company’s future profitability. Wall Street and the news media may dismiss Invitae’s characterization that the errors should affect only 2 to 15 patients (out of 50,000 genetic tests) as not material and continue to cover the company as usual.
How Will Clinicians React?
Among clinicians, Invitae’s current woes may have consequences over many years. Some physicians, genetic counselors, and other clinicians will consider Invitae’s omission of the MSH2 Boland inversion mutation to be minor—a hiccup in a field that advances through trial and error. But there will be some clinicians who distrust Invitae enough to refer their tests to other lab companies.
The next question is how lab regulators will react. Lab regulators have a history of being tough when such errors come to light. When they learn of these failures, government regulators conduct rigorous inspections in an effort to uncover any problems that might otherwise go undetected.
Federal and state inspectors recognize that it is extraordinary for any laboratory to have performed inaccurate tests on 50,000 patients over 11 months and never detect the systemic error through its quality control program.
Also, government lab regulators understand the significance of a systemic error involving such a large number of patients and the extent of the potential harm such an error can cause, even if only a few patients are affected.
Pathologists and lab administrators will watch closely to see if officials inspect the Invitae lab in San Francisco, what deficiencies they identify, and what enforcement actions they take. Any regulatory action may set new precedents in how genetic testing laboratories are inspected.
For lab directors, the lessons to gain from this episode will include what they can learn to improve their own lab’s quality control programs, what deficiencies federal and state regulators identify, and how to eliminate those deficiencies in their own labs through improved quality control procedures.
In important ways, this problem at Invitae has the potential to cause the entire genetic testing industry to undergo more regulatory scrutiny and tougher inspections of their laboratories. New and tougher regulations may result and the FDA will have this episode to support its efforts to gain congressional approval to regulate laboratory-developed tests.
Finding the 1 patient in 1,000,000 with Rare Mutation Is the Main Goal of Every Genetic Testing Lab
IN THEIR PUBLIC COMMENTS about the systemic error in the genetic tests performed for 50,000 patients, executives at Invitae Corporation emphasize that they estimate that only 2 to 15 patients received a false negative report.
If their message to the media and investors is that this is not a systemic error that should cause concern about the integrity of the company’s genetic testing activities and, if the small number of patients who got false negative results for a rare mutation associated with inherited cancers supports that conclusion, there are others in the genetic testing industry who disagree with that view.
Several medical directors at genetic testing laboratories expressed their personal opinion to THE DARK REPORT that the problem represents an important failure of the genetic testing company and should be taken seriously.
One lab industry executive says that the primary service every genetic testing laboratory provides to physicians and patients is its ability to accurately and consistently identify rare mutations that would be clinically-relevant for the individual patient.
“Think of it in this way,” stated Richard Faherty, formerly Executive VP, Administration, for BioReference Laboratories, Inc. and its GeneDx subsidiary. “The essential product of a genetic testing laboratory that says it detects rare mutations for inherited genetic disease is the ability to always find that one mutation in a million for the patient. After all, isn’t that why the referring physician and the patient ask a genetic testing lab to identify whether any such mutations are present?
“Thus, for any lab like Invitae to tell its physicians that the genetic test performed for ‘only a few patients’ may have reported a false negative result betrays the quality and accuracy that all physicians, patients, and their families expect of our labs,” explained Faherty. “Remember that what physicians and patients do with these results is very drastic because it determines how therapies such as surgery, radiation, and cancer drugs will be used.
“This is why I consider it a massive failure anytime a genetic lab—whether large or small—misses rare mutations in even a small number of patients because of a failure at the bench,” added Faherty.