Monday, June 01, 2020

U.S. coronavirus testing stalled for six weeks. A small German lab made 1.4 million tests in that time.

Mar 17. 2020
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By The Washington Post · Peter Whoriskey, Neena Satija · NATIONAL, WORLD, HEALTH, EUROPE

 When Olfert Landt heard about the novel coronavirus, he got busy. The founder of a small Berlin-based company, the ponytailed 54-year-old first raced to help German researchers come up with a diagnostic test and then spurred his company to produce by the end of February more than 1.4 million tests for the World Health Organization.

"My wife and I have been working 16 hours a day, seven days a week, ever since," said Landt by phone about 1 a.m. Friday, Berlin time. "Our days are full."

By contrast, over the same critical period, U.S. efforts to distribute tests ground nearly to a halt, and the country's inability to produce them left public health officials with limited means to determine where and how fast the virus was spreading. From mid-January until Feb. 28, fewer than 4,000 tests from the U.S. Centers for Disease Control and Prevention were used out of more 160,000 produced. 

The United States' struggles, in Landt's view, stemmed from the fact the country took too long to use private companies to develop the tests. The coronavirus pandemic was too big and moving too fast for the CDC to develop its own tests in time, he said.

"There are 10 companies in the U.S. who could have developed the tests for them," Landt said. "Commercial companies will run to an opportunity like this."

As the coronavirus continues to spread across the United States, causing more than 70 deaths and more than 4,000 confirmed cases, the struggles that overwhelmed the nation's testing are becoming clearer.

First, the CDC moved too slowly to tap into the expertise of academia and private companies such as Landt's, experts said. For example, it wasn't until last week that large companies such as Roche and Thermo Fisher won approval from the Food and Drug Administration to produce their own tests.

While FDA and CDC officials have attributed some of the testing delays to their determination to meet exacting scientific standards they said were needed to protect public health, the government effort was nevertheless marred by a widespread manufacturing problem that stalled U.S. testing for most of February.

The CDC has yet to fully explain the nature of the manufacturing problem but told The Washington Post on Monday that the design of the test could also have resulted in flawed tests.

But the U.S. Department of Health and Human Services, which oversees the CDC, said earlier this month that it is investigating the defect in many of the initial coronavirus test kits.

It has been long-standing practice for CDC scientists in emergencies to develop the first diagnostic tests, in part because the CDC has access to samples of the virus before others, officials said. Later, private companies that win FDA authorization can scale up efforts to meet demand.

In responses for this report, CDC spokesman Benjamin Haynes said in a statement: "This process has not gone as smoothly as we would have liked. . . . CDC has a responsibility to ensure that all CDC laboratory research and development activities, testing processes, and data are the highest possible quality and are traceable, reproducible, and documented with appropriate rigor."

He said the manufacturing problem may have arisen because of the test's design or because of contamination.

Finally, acknowledging that there "is a great need for test manufacturers to rapidly make testing available," the statement said that "commercial labs are working to develop their own tests and hopefully will be available soon for clinical settings throughout the country."

But critics say government officials should have moved much more quickly to bring on expertise from outside the CDC.

"The CDC has good scientists and they are proud," Landt said. "But in this situation, they took the wrong approach."

- - -

At the very beginning, U.S. efforts to develop a diagnostic test for the coronavirus kept pace with the rest of the world.

Shortly after publication of the virus's genome in early January, German researchers announced that they had designed a diagnostic test. Then, within days, scientists at the CDC said they'd developed one, too, and even used it detect the first U.S. case.

"We actually do have laboratory diagnostics here at CDC that are stood up," Nancy Messonnier, the CDC's director of the National Center for Immunization and Respiratory Diseases, told reporters Jan. 17.

From there, however, U.S. efforts fell behind quickly, especially when compared with the efforts of the WHO, which has distributed more than 1 million tests to countries around the world based in part on the method developed by the German researchers.

As early as Feb. 6, four weeks after the genome of the virus was published, the WHO had shipped 250,000 diagnostic tests to 70 laboratories around the world, the agency said.

By comparison, the CDC at that time was shipping about 160,000 tests to labs across the nation - but then the manufacturing troubles were discovered, and most would be deemed unusable because they produced confusing results. Over the next three weeks, only about 200 of those tests sent to labs would be used, according to CDC statistics.

In fact, the U.S. efforts to distribute a working test stalled until Feb. 28, when federal officials revised the CDC test and began loosening up FDA rules that had limited who could develop coronavirus diagnostic tests.

During that critical interval, the CDC repeatedly assured the public that progress was being made, even as public health officials around the country began to raise alarms about the shortage of tests.

In January, CDC officials boasted during the coronavirus briefings that the United States has "one of the strongest public health systems in the world."

At briefing on Feb. 12, Messonnier said "rapid development of a diagnostic and rapid deployment to the states" is "clearly a success."

On Feb. 14, she said: "We can be proud. . . . We moved quickly."

On Feb. 21, Messonnier acknowledged problems with the testing kits but described the issues as "normal."

But by that point, public health labs around the nation had run very few of the CDC tests, according to the agency. Health officials across the country began pleading for a test that worked, or at least the authorization to use another test.

- - -

In the absence of tests, the calls for the United States to tap into the expertise of academia, hospitals and private companies, such as Landt's, grew more insistent.

"It took [the CDC] a while to come up with the test, honestly," said Alex Greninger of the University of Washington.

His lab had developed its own test and began seeking approval to use it on patients on Feb. 18. But that test, along with others that had been developed in various academic centers and hospitals, could not be used on patients until the FDA relaxed its testing rules on Feb 28.

He noted that many of the state public health labs had also figured out how to use the CDC test properly - by tossing one of its components - but were not allowed to actually do so until the FDA approved the workaround that same day.

"We had all these state public health labs that had a perfectly good [test] on their hands, and they knew it, they were upset," Greninger said.

"What surprised me the most was to hear how much emphasis there is at CDC on quality control - to the point where, in my opinion, it really compromised surveillance," said Michelle Mello, a professor of law and medicine and Stanford who recently wrote a paper about the delays in testing for coronavirus in the United States. "You can't track what you don't see."

On March 7, FDA Commissioner Stephen Hahn stressed the importance of quality, noting that diagnostic tests in some other countries have been flawed. He did not specify which countries he meant, but China's test may have produced lots of false positives, according to a recent publication by Chinese researchers.

"What's important here is that we have a test that the American people can trust," Hahn said.

But even a small firm, like Landt's, is capable of producing a lot of high-quality tests and could have helped the efforts in the U.S., Landt said. His company, known as TIB for TIB Molbiol Syntheselabor GmbH, based their tests on the methods the German researchers published in January.

Though it has just 55 employees globally, TIB had experience in developing tests for SARS and the swine flu. It began producing the coronavirus tests in mid-January, just days after the Chinese researchers posted the virus's genome, Landt said. It can produce about a million of them a week.

As wearying as his schedule has been, Landt said, "I like the feedback from people."

- - -

Exactly what went wrong with the CDC's first tests in the first critical weeks hasn't been fully explained by the agency, aside from the possibility that the design was flawed or that the tests were contaminated.

While such diagnostic tests can vary in the specifics, they typically involve trying to match the genetics of a patient sample, taken from nasal and throat swabs, against those of the virus.

In the case of the CDC method, the test consisted of attempts to match a patient sample against three distinct pieces of the virus's genetic code. A patient was declared to have coronavirus if each of those three attempts came back as a match.

The trouble with the CDC test arose because the third attempt at a match, known as the N3 component, produced an inconclusive result even on known samples of the coronavirus.

While the cause of the problem in the CDC test may be unknown, it meant that in the weeks before Feb. 28, the public health labs were left waiting for a usable test.

By Feb. 8, public health labs were notifying the CDC of troubles with the test, and four days later, about a week after the first CDC tests had shipped, officials acknowledged the problem during a news conference.

"Some of the states identified some inconclusive laboratory results," Messonnier said Feb. 12. "We are working closely with them to correct the issues and as we've said all along, speed is important, but equally or more important in this situation is making sure that the laboratory results are correct."

In the following weeks, CDC officials repeatedly said they were working to resolve the manufacturing problem. Then, on Feb. 28, the agency announced that it would just scrap the N3 component of the test that had been causing trouble. Officials also contacted a private company called Integrated DNA Technologies and asked it to make new test kits, the company said.

While the problems with the CDC test persisted, the vast majority of testing had to be done at the CDC's Atlanta lab, and the numbers being tested were woefully below what experts said was needed.

As late as Feb. 27, 203 specimen tests had been run out of state labs; another 3,125 had been run out of the CDC.

James Lawler, director of the global center for health security and an epidemiologist at the University of Nebraska Medical Center, was one of the infectious disease specialists who flew out to meet the Diamond Princess cruise ship passengers in Japan and flew back with them to the United States. Lawler said the problem was not just in the manufacturing of the test but in the design.

In his view, the test has design problems that make it too difficult for many labs to make it work unless they have perfect conditions.

He said that even though the University of Nebraska Medical Center - a world renowned infectious-disease institution that houses the state's public health lab - was able to get the CDC version of the test to work, the Nebraska center developed its own test based on the German lab design published by the WHO.

"It's very nuanced and complicated to make a diagnostic test," Lawler said. "If you don't go back and fix things . . . and realize, 'Hey, maybe I should try a different target,' that's when you can run into problems. . . . Everything down to the details of the humidity and temperature in some people's laboratories is going to be different."

If the design of the test is flawed, he said, "all of those conditions may come into play. Some people have been able to get reproducibly good results and others haven't."

- - -

Shortly after Feb. 28, when CDC officials announced the decision to reconfigure the CDC test, the number of those tests run by public health labs soared, from roughly 25 or fewer per day to as many as 1,500. At the same time, authorities were allowing other facilities to use their own tests - including the Cleveland Clinic, Stanford University and Greninger's at the University of Washington.

Even so, complaints of testing scarcity continued to roll in last week. And even as tests become more widely available, experts and officials have cautioned that a backlog will continue due to a critical shortages: swabs to collect patient samples, machines to extract the genetic material from the swabs, workers qualified to run the tests.

Even if those problems are resolved, however, those critical early delays, when the CDC was struggling to issue tests to the states, significantly damaged efforts to contain the spread of coronavirus, experts said.

In a CDC tele-briefing on Feb. 29 that included some local and state public health directors, local officials lamented the initial inability to test. A reporter asked: "Did the lack of testing capabilities delay finding out who these cases were, particularly the person who died?"

In answer, Jeff Duchin, the public health chief in King County, Washington, where 37 deaths have been reported, suggested that the lack of tests was critical, in addition to the fact that authorities had limited who could be tested. Initially, they had said tests would only be used for those who had traveled in affected regions of the globe or had otherwise been in contact with an infected person.

"So, you know, if we had the ability to test earlier, I'm sure we would have identified patients earlier in the community, possibly at hospitals, but we were also looking at not only availability of testing but whether patients met criteria for testing," Duchin said." So, given the fact that we just recently acquired our availability of testing and new criteria were published, this person was brought to our attention."

Thomas Frieden, an infectious disease physician who served as CDC director under President Barack Obama, called on Sunday for an "independent group" to investigate what went wrong with the CDC's testing process. He said that in the past, the CDC moved quickly to produce tests for diseases such as H1N1, a.k.a. swine flu.

"We were able to get test kits out fast," Frieden said on CNN. "Something went wrong here. We have to find out why so we can prevent that in the future."

Frieden said the agency has been muzzled under President Donald Trump and despite the multitude of problems with the rollout of testing, "the CDC is still the greatest public health institution in the world."

 

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