In late April 2009, Dr. Joshua Sharfstein, then the Food and Drug Administration’s principal deputy commissioner, received an urgent weekend phone call from the director of the Centers for Disease Control and Prevention.
Dr. Rich Besser told Sharfstein that the CDC — and by, extension, public health departments nationwide — faced a serious problem.
Less than two weeks earlier, the CDC had identified a virulent new strain of swine flu in a 10-year-old patient in California. Within days, the novel strain cropped up in another California child, two patients in Texas, a cluster in Mexico and an outbreak at a New York high school. Dubbed H1N1, the virus was spreading fast, with all signs pointing toward a pandemic.
Widespread diagnostic testing was needed immediately to understand the scope of the nation’s outbreak, Sharfstein recalled Besser telling him. But there was one big catch.
“He said the test was going to take at least six months to review, but we couldn’t wait that long,” Sharfstein, now a vice dean of public health at Johns Hopkins University, told The Seattle Times.
Within 48 hours, Sharfstein and a team of FDA lawyers found a way to get tests out quickly through an existing FDA process called “Emergency Use Authorization.” The novel use of the “EUA,” a process typically aimed to give the FDA some oversight over unapproved medical devices needed for emergencies, marked the first time it was tapped for a public health diagnostic test.
That regulatory innovation, which allowed the swine flu test to bypass typical FDA trials that can take more than a year, has since served as a national model for pandemics, including responses to Ebola, Zika and other emerging viruses.
But past successes with the emergency authorization process also set the stage for what would be its biggest failure: Quickly getting reliable diagnostic tests for the novel coronavirus into labs nationwide last month, before the fast-spreading infection that had savaged countries around the world could do so in the U.S.
With the CDC always serving as the emergency authorization applicant and test distributor on behalf of scores of domestic public health labs, a key weakness was overlooked: If something went wrong with the CDC’s tests, the labs that relied on them would be rendered helpless and without immediate testing alternatives.
“We had only needed to use the EUA process a few times before, and it really had worked,” said Scott Becker, chief executive director of the Association of Public Health Laboratories, which represents 120 public health labs nationwide. “But in all the previous responses, we’ve never had the test fail right out of the gate.”
Many public health labs, after receiving the first batch of CDC diagnostic panels in early February, started reporting problems with validating test results. The labs were hamstrung while they waited for the CDC to fix the problem.
The process took nearly three weeks, a lag time during which labs couldn’t try other testing options that hadn’t won the FDA’s clearance. Meantime, commercial labs without emergency authorizations were sidelined.
“We didn’t see a benefit for individual labs going through that [EUA] process because the CDC always had them covered,” Becker said. “I do think in the future, we’re going to look very carefully at having multiple tests available to us because we don’t want to be where we were, which was a single point of failure.”
The testing shortage hurt initial efforts to track and contain coronavirus outbreaks in Washington and other states, public health officials have acknowledged.
The CDC, in a statement this week, said: “This process has not gone as smoothly as we would have liked, but there is currently no backlog for testing at CDC and since Friday, February 28, 2020, more and more state labs are coming online.”
But once the nation fell behind in testing, the problems have only persisted. A rapid scale-up of testing capacity to catch up to the coronavirus has strained health care systems and depleted stockpiles of lab materials. People across the nation, including seriously ill patients, high-risk nursing home residents, even medical professionals exposed to the sick, continue to complain they can’t get tested.
Some experts now say the authorization process that worked when responding to past pandemics became a bottleneck of restrictions for coronavirus testing, when it didn’t need to be.
The FDA disputes that.
“Laboratories always have had the ability to develop tests from day one,” FDA spokeswoman Stephanie Caccomo said in an email late Wednesday, adding the agency has worked with manufacturers and labs since January.
“We have encountered examples where labs did not understand the FDA process and mistakenly believed there was more work involved, or just did not even realize that they could develop a test in the first place,” she added.
A flexible process
Each pandemic has its own characteristics, so it’s the FDA’s judgment call on what conditions to apply when granting an emergency use authorization to fast-track diagnostic tests.
“The EUA is a very flexible process,” Sharfstein said. “Basically, the standard is the FDA looks at the emergency and decides that the benefit exceeds the risks.”
Driving the process, Sharfstein said, are questions of how much time there is to respond and what’s the right thing to do. “You basically tailor your approach from there,” he said.
Just before the 2009 swine flu outbreak, the CDC had developed a “five target assay” to test for various influenza strains, receiving FDA approval to distribute the test kits under conditions that it first train lab workers to use them.
That training already had happened when the CDC submitted an emergency authorization application for swine flu. After the FDA quickly approved it, kits with the swine flu test began shipping on May 1, 2009. By September, more than 1 million tests were deployed to more than 120 local and state public health labs and 250 others worldwide.
“The test was already approved, so it was easy for the CDC to just swap in H1N1 as a strain in that test,” Sharfstein said. “We had surveillance out very quickly and other (commercial) tests soon followed.“
The novel coronavirus isn’t a flu, and so a new diagnostic test needed to be developed. Scientists in China, where the disease originated, had identified and posted the virus’s gene sequence on the World Health Organization website. German scientists, in turn, used it to design a test and shared it with WHO on Jan. 17 so that any lab could replicate and use it.
“Any virologist around the world that wants to develop a test can do that, but we can’t,” said Becker, the public health labs association director. “In the United States, because the emergency was declared, labs had to have [emergency authorization] applications approved first.”
The CDC typically develops the first diagnostic tests for pandemic emergencies, Becker said. After public health labs scale up, university and commercial labs follow with their own tests to help meet demand after obtaining FDA clearance. The CDC designed its test and posted it on Jan. 24.
Like the German test, the CDC’s test was based on polymerase chain reaction, or PCR, a technique that screens for bits of the virus’s genetic code in nose or throat swabs collected from patients.
On Feb. 3, the CDC submitted its application to the FDA, with 400 test kits, each capable of testing 1,000 specimens, ready to ship to domestic and international labs, according to a CDC timeline provided this week.
The FDA granted approval a day later with conditions that allowed testing for a narrow group of high-risk patients with symptoms, such as those who had traveled to China or come in close contact with an infected or exposed person.
By then, just 11 cases of COVID-19, the illness caused by the novel coronavirus, had been confirmed in the U.S. by the CDC’s own limited testing. Some public health experts, including former FDA Commissioner Scott Gottlieb, started calling for faster and more widespread testing to detect and contain potential outbreaks.
The first 90 CDC test kits went out on Feb. 6 and 7 to labs in all 50 states and Washington, D.C. By Feb. 8, some public health labs started reporting problems with validating the tests, finding “sporadic reactivity in the negative control,” the CDC said. That resulted in inconclusive test results.
The faulty tests affected most public health labs, including Washington’s Department of Health (DOH) laboratory. Testing at all but eight labs nationwide ceased while the CDC tried to fix the problem, Becker said.
As the testing lapse dragged on for two and a half weeks, lab officials started getting “very anxious that we did not have eyes on the community,” Becker said. By then, the virus had been spreading for weeks.
A lost month of testing
During the lag, Washington’s Health Department discussed options with scientists working with the Seattle Flu Study and the University of Washington Medical Center’s virology department.
“Each of them had developed an assay and we really tried hard to see if we could get those tests approved so that we could use them to start testing people for COVID-19,” said Dr. Kathy Lofy, the state’s public health officer.
But only CDC had the FDA’s emergency authorization for a diagnostic test.
Nonetheless, the Seattle Flu Study, a Bill Gates-backed project that collects nasal samples voluntarily from area residents to track the spread of viruses, started performing unauthorized tests for coronavirus at the end of February, a fact first reported by The New York Times. The tests identified a Snohomish County teen as Washington’s second COVID-19 patient, and other cases indicating indicated community transmission of the virus.
On Feb. 24, Becker’s lab association, which represents 120 public health labs, also couldn’t wait any longer. In a letter, he and Texas state health lab director Grace Kubin urged FDA Director Stephen Hahn “to consider enforcement discretion” to allow state and local labs to create and use their own test.
Two days later, on Feb. 26, Hahn responded that an emergency authorization application would still be necessary to ensure “the FDA’s appropriate oversight.” But he offered the lab association a “template to streamline the process” for receiving clearance for a testing protocol.
Later the same day, FDA and CDC officials informed Becker that the CDC had finished re-manufacturing test kits that would go out to labs the next day. The new batch would include only two chemical reagents — used in reaction mixes to analyze samples — and would not contain a third reagent with which most labs had experienced problems in the initial kits.
The FDA also allowed labs to discard that flawed reagent from the original kits and immediately begin using them again to test for COVID-19.
The FDA eliminated more red tape on Feb. 29, allowing certified private and university labs, including the UW’s virology lab, to start testing for coronavirus before receiving an emergency authorization. The labs were required to first self-validate tests and apply for the authorization within 15 days.
“All tests should be validated prior to clinical use,” said Caccomo, the FDA spokeswoman. “The policy we published on February 29 did not change this, and any good laboratory would do this anyway.“
Widespread testing finally began to ramp up.
At the end of February, a lost month of testing, U.S. public health labs had tested just 3,955 specimens to detect 377 cases nationwide, CDC statistics show.
While problems still persist, the fixed kits and eased restrictions helped get more than 18,000 additional specimens tested and 879 new cases identified during the first 11 days of March alone.
‘The big question’
The CDC has’t fully explained what caused the test kit problems, but spokesman Scott Pauley said in an email the issue “may include assay design or contamination.”
An investigation remains ongoing.
The CDC, which manufactured the test kits in its Atlanta-based lab, “is not really a large-scale production facility,” Becker said.
Before the CDC re-manufactured its kits, it contracted “with 2 large commercial manufacturers” to ensure reagent availability for the new tests, Pauley’s email said. One of those was Iowa-based Integrated DNA Technologies, Becker said.
Becker believes the process for rolling out emergency diagnostic tests should be reviewed, with considerations to make additional testing options available for public health labs other than only the CDC’s tests.
But the FDA’s initial emergency use authorization didn’t have to make the CDC a chokepoint for testing, Sharfstein said.
Conditions can “be as flexible or restrictive as the FDA approves it to be,” even allowing the CDC and multiple private and public health labs to design and use tests simultaneously, he said.
The FDA, in fact, approved at least seven other testing emergency authorizations this month.
So, why did the FDA take the approach it did?
“That’s the big question,” Sharfstein said. “I think they weren’t anticipating the scale of the situation. If you asked them if they could do it again, they probably wouldn’t choose this route.”
The FDA’s spokeswoman, who didn’t answer whether the agency took too long to ease testing restrictions, countered that the agency has been readily supportive of widespread testing.
“FDA’s engagement has been flexible and has supported the efforts of labs around the country and the rapid expansion of COVID-19 testing overall,” she said.