FDA file photo

This Scientist Created a Rapid Test Just Weeks Into the Pandemic. Here’s Why You Still Can’t Get It.

Irene Bosch developed a quick, inexpensive COVID-19 test in early 2020. The Harvard-trained scientist already had a factory set up. But she was stymied by an FDA process experts say made no sense.

When COVID-19 started sweeping across America in the spring of 2020, Irene Bosch knew she was in a unique position to help.

The Harvard-trained scientist had just developed quick, inexpensive tests for several tropical diseases, and her method could be adapted for the novel coronavirus. So Bosch and the company she had co-founded two years earlier seemed well-suited to address an enormous testing shortage.

E25Bio — named after the massive red brick building at MIT that houses the lab where Bosch worked — already had support from the National Institutes of Health, along with a consortium of investors led by MIT.

Within a few weeks, Bosch and her colleagues had a test that would detect coronavirus in 15 minutes and produce a red line on a little chemical strip. The factory where they were planning to make tests for dengue fever could quickly retool to produce at least 100,000 COVID-19 tests per week, she said, priced at less than $10 apiece, or cheaper at a higher scale.

Bosch’s prototype attracted a top Silicon Valley venture capital firm, which pitched in $2 million.

“We are excited about what E25Bio is capable of shipping in a short amount of time: a test that is significantly cheaper, more affordable, and available at-home,” said firm founder Vinod Khosla. (Disclosure: Khosla’s daughter Anu Khosla is on ProPublica’s board.)

On March 21 — when the U.S. had recorded only a few hundred COVID-19 deaths Bosch submitted the test for emergency authorization, a process the Food and Drug Administration uses to expedite tests and treatments.

A green light from the FDA could have made a big difference for the many Americans who were then frantically trying to find doctors to swab their noses, with results, if they were lucky, coming back only days later.

But the go-ahead never came.

In the months that followed, Bosch responded to repeated requests from FDA reviewers for data and studies. When the agency finally put out guidance that summer about the performance over-the-counter home tests needed to meet, officials required that such tests be nearly as sensitive as the lab tests used to definitively determine whether a patient has COVID-19.

That standard proved difficult to meet. Rapid tests are usually sensitive enough to detect viral antigens when someone has enough of them to be able to spread the disease. Such tests are not as good at picking up cases in either earlier or later stages of infection, when viral loads are lower.

Bosch’s tests missed the FDA’s high bar. It wasn’t until the spring of 2021 that much larger companies were able to design similar tests — relatively inexpensive, over-the-counter rapid tests — that the agency found acceptable.

“You could have antigen tests saving lives since the beginning of the pandemic,” said Bosch, sitting in her lab at MIT. “That’s the sad story.”

As ProPublica recently detailed, many companies with at-home tests have been stymied by an FDA review process that has flummoxed experts and even caused one agency reviewer to quit in frustration.

While E25Bio’s test didn’t catch quite as many cases as those now on the market, it could have been used to catch superspreaders, with warnings that a negative result wouldn’t rule out infection. Experts told us that the test could have been a vital public health tool had it been produced in the millions in 2020 just as COVID-19 was racing across the country undetected.

“Since we didn’t have other options, it would have been a very good test,” said Michael Mina, an epidemiologist who followed E25Bio’s early progress. “If we were going to war, and somebody was invading us, and we had a bunch of revolver pistols, and we didn’t yet have the shipment of machine guns, hell yeah, you’re going to pick up the revolver pistol. You do what you can when you need to in an emergency.”

Three other experts reviewed Bosch’s submissions at ProPublica’s request and agreed that her test approached what is now considered acceptable for over-the-counter tests.

Mina and others have been calling for an embrace of rapid testing since the pandemic’s early days, saying that tests should be ubiquitous and cheap enough that people could stock them in their medicine cabinet, like aspirin or Band-Aids. Althoughnot a panacea, rapid tests can slow the spread of COVID-19 when used repeatedly and when the infected follow instructions to isolate,manystudiessuggest.

After not showing urgency on the issue for much of the past year, the Biden administration has moved recently to boost production and lower prices. Facing a huge new wave of cases and an increasing outcry about shortages of tests, Biden announced Tuesday that 500 million more at-home tests would be distributed by mail, starting in January.

David Paltiel, a professor at the Yale School of Public Health, said a significant part of the problem is that the FDA created a detailed roadmap for tests that give patients a close-to-definitive answer on whether they have COVID-19, but never created a separate framework for rapid tests that serve a different purpose: helping people get frequent, fast evidence of whether they may be contagious.

“The former are tests of infection; the latter are tests of infectiousness,” Paltiel said. “They both share the same regulatory pathway — a pathway that was designed with diagnostic testing in mind and is littered with requirements that make no sense for the purpose they serve.”

He added, “It’s an outrage that rapid tests aren’t dirt cheap and plentiful on grocery store shelves.”

The FDA declined to comment on individual test submissions, but said in a statement that it has worked to authorize “accurate and reliable” home tests since the beginning of the pandemic.

“Unfortunately, many submissions the FDA has received for home tests include incomplete or poor data, and it is the FDA’s responsibility to protect the public health by declining to authorize poorly performing tests or those without complete data,” the agency said. “We have also worked interactively with many developers to resolve concerns when data was incomplete or unclear, or to find solutions to issues that arose during review. If the FDA received a home test that the data and science supported in early-to-mid 2020, we would have quickly authorized it.”

Bosch has since moved on to start a new venture focused on helping other test developers conduct trials that meet the FDA’s standards. This winter, she’s working with the housing authority in the high-poverty Boston suburb of Chelsea to conduct a trial using several tests that have been authorized in other countries, but not America. The goal: to demonstrate that such tests can be effective when deployed for free, in conjunction with education and outreach.

“The next thing is frequent testing for communities that need it,” Bosch said. “How do we flood the market with a $2 test that is as good as a $20? We’re doing it in Chelsea. We should be an example for the whole country.”

American medical device regulators have never been enthusiastic about letting people test themselves.

In the 1980s, the FDA banned home tests for HIV on the grounds that people who tested positive might do harm to themselves if they did not receive simultaneous counseling. In the 2010s, the agency cracked down on home genetic testing kits, concerned that people might make rash medical decisions as a result.

But the FDA wasn’t an obstacle to Bosch’s work on tropical diseases, since the tests were mostly needed in places like the Brazilian Amazon, where infected mosquitoes are hard to escape. The National Institutes of Health thought Bosch’s tests had enough potential to give E25Bio $1.8 million for the project.

So when the pandemic struck, the small company decided to use its expertise for the new threat. Within a few weeks, Bosch and her colleagues developed antibodies that could detect the presence of proteins attached to the new coronavirus.

In her previous work, Bosch had found that tests of this type could be validated in the lab, so she ordered up some samples of the SARS-CoV-2 virus and ran two different types of antigen tests on them. She found that both worked fairly well, and packaged up all her evidence and sent it to the FDA, with little guidance on what would pass muster.

Shortly after, an FDA reviewer told her she’d need to conduct a clinical trial, which would take months. “My first huge surprise was when they said, ‘Nope, none of your validations are going to pass for an EUA,’” Bosch said.

The next challenge was that the accuracy of antigen tests would be measured by how they compared to a different type of diagnostic: the polymerase chain reaction, or PCR, test, which is considered the “gold standard” for finding coronaviruses. Many see that as an unproductive comparison, given the fact that PCR detects remnants of the virus, which may persist for many days after the infection ceases to be a threat.

“When you’re PCR testing, you’re testing for the presence of viral genetic material,” said Hannah Mamuszka, the CEO of Alva10, a company that helps diagnostics manufacturers prove their value for insurers. “When you’re antigen testing you’re testing for presence of a protein on the surface of the virus,” she said. “Those are obviously not the same thing. So it’s really confounding that the FDA has had such a hard time communicating what they need, and defining what a test would need to look like to be used at home.”

Nevertheless, by April 2020, E25Bio had lined up a trial with three hospitals in Florida. They found the test identified 80% of the swabs that a PCR test had shown to be positive (known as sensitivity) and 94% of the negatives (known as specificity).

The FDA wanted to see fewer false positives, even though people who test positive on an antigen test are usually advised to confirm it with a PCR. And while the overall sensitivity of E25Bio’s test was lower than other tests would later demonstrate, it measured 100% for people with higher viral loads — those most likely to be infectious.

Bosch was in frequent contact with her assigned reviewer at the FDA, and even talked to Tim Stenzel, the head of the agency’s office that vets diagnostic tests. The Bill & Melinda Gates Foundation gave E25Bio another $500,000 to continue research and development.

But at the end of July 2020, the FDA came out with a template that laid out the expectation that tests available for home use without a prescription would reach 90% overall sensitivity — that is, antigen tests would pick up nine out of ten positive tests that a PCR identified. Bosch knew her tests couldn’t meet that standard. And without an EUA for home use, they wouldn’t be able to serve their intended function.

Already, plenty of models had illustrated the importance of frequent testing, including one co-authored last year by Yale’s Paltiel with Rochelle Walensky, now head of the Centers for Disease Control and Prevention. In September 2020, as chief of infectious diseases at Massachusetts General Hospital, Walensky argued that antigen tests were actually most useful for pinpointing people at their most infectious.

In fact, the utility of that approach was being tested at Bosch’s own former workplace. Beginning in the late summer of 2020, a coworking lab space in Cambridge where E25Bio had launched started a trial with 257 of its users who agreed to take both the antigen rapid test at home and a PCR test twice a week. (This was also closer to a home use scenario than the Florida hospitals study, in which COVID-19 was more prevalent and tests were administered by medical professionals.)

A peer-reviewed paper based on the results showed overall sensitivity of 79%, and that the rapid test picked up nearly all of the positives later detected by a PCR in the first few days after symptoms appeared, allowing infected people to stay out of the office as soon as they knew.

But the FDA does not consider test performance data broken out by how much virus the subjects have in their systems, saying the typical method for measuring it is inconsistent. Nor did the agency initially authorize tests on the condition that they be sold in packs of more than one, with instructions to use them sequentially to catch any fast-moving infections.

Bosch wasn’t the only one to be tripped up by the new standard. In mid-September 2020, Stenzel said on his weekly town hall call with test developers that his office had received zero applications for home use tests, a month and a half after putting out the template, despite his insistence that the agency was willing to be “flexible.”

Meanwhile, a $666 million NIH program to accelerate the approval and production of new COVID-19 tests funded mostly PCR tests in 2020.

The antigen tests that did make it into the NIH program in the first threefundingrounds — including one made by Quidel, a public company that multiplied its profits by tenfold in 2020 over the previous year — generally had to be processed in labs or required expensive analyzers.

One of few simple antigen tests to win government support, made by Maxim Biomedical, still hasn’t submitted an EUA application, according to chief operating officer Jonathan Maa. Another grantee, Ellume, was authorized for nonprescription home use in December 2020. But it took months to go into widespread production, and still costs $39, if you can find it.

Toward the end of October 2020, Bosch received a 48-hour ultimatum from the FDA for a response to a request for additional data. She had answers to the agency’s questions, but didn’t quite make that deadline.

By the time she replied, the FDA had already closed her application. “You call and they say, ‘Oh sorry, the clock started and we can’t stop it,’” she said.

Soon after, the company’s leadership asked her to resign. The company continues to operate, but hasn’t obtained FDA authorization for any tests. “As we commercialize our COVID-19 rapid tests internationally, we are also focused on developing the next generation of rapid tests for consumer diagnostics,” an E25Bio spokesperson said, while declining to comment on Bosch’s departure or its current product pipeline.

“All our life, day in and day out, went to make antigen tests,” Bosch said. “It was tragic, because it was all because the FDA decided to be so harsh in their responses that investors said, ‘Oh, there’s no way she will pull it out.’”

E25Bio’s travails with the FDA didn’t stop Bosch from putting her expertise to use.

In early 2021, she started talking to the city of Chelsea about running a trial that could show how rapid antigen testing — even with the types of tests that the FDA had rejected — could be rolled out in a high-risk community. In the spring, when infection rates in Chelsea were among the highest in the nation, many residents had had a difficult time accessing PCR tests, because the places administering them often dissuaded immigrants by requiring identification.

Chelsea officials agreed, and Bosch secured donations of tests from five manufacturers that had been authorized in Britain, Germany, India or Korea, but none yet in the U.S. (They can still be used here for research purposes.) She said she has validated them in her lab and found them to be about as accurate as BinaxNOW, the FDA-authorized home test made by medical device giant Abbott Laboratories.

“If they have a budget for next year to do frequent testing, this will be an accomplishment,” Bosch said. “I wanted to show to the world that an experimental device is just as good as any other already-approved FDA test.”

So for the past few months, Bosch has canvassed three buildings owned by the local housing authority. Bosch, who is from Venezuela, puts on salsa music and explains in Spanish how the program will work.

The trial began in earnest last week, with study administrators walking newly enrolled subjects through using the tests. In a building reserved for elderly and disabled people, residents entered with walkers and in flip-flops to learn how to swab their noses, put the swabs in a vial of solution, squeeze a few drops onto a pad and wait anxiously for the single line to appear that would indicate a negative result.

Most were able to take a picture of the results with their phones and upload them using a special app, which they’ll continue to do in their homes each week.

The FDA frowns upon this kind of instruction in trials for at-home tests — users are supposed to be able to execute the test without training. But in reality, many need support.

For the nonprofit that helped launch the effort, the Center of Complex Interventions, the important part is demonstrating that rapid tests can work when used as part of a coordinated testing regime to address specific situations: right before people gather indoors or after an exposure to an infected person, for anyone in a high-risk job, for people in crowded living situations, or for those who have health risk factors. People in all of those situations are concentrated in Chelsea’s housing authority buildings.

“It’s a lot different than saying, ‘Let’s roll it out to everybody,’” said Karthik Dinakar, who is leading the project. “It all has to be connected in a way that makes people feel like they’re participating. The goal for us is to make the community safer, and also shift the mindset to a new equilibrium.”

Joshua Sharfstein, a vice dean at Johns Hopkins University’s Bloomberg School of Public Health who used to be principal deputy commissioner of the FDA, said that rapid tests could have been authorized earlier with these kinds of protocols in mind.

“There was no testing strategy,” Sharfstein said, outlining the opportunity that America missed to use a variety of tests for the purposes to which they were best suited. “What they could have done is to say, ‘Here are the six uses of tests. You’re sick, you’re exposed, you’re trying to maintain people on a campus. What’s the performance of test that you would need?’

“Just think how amazingly helpful that would be,” he finished, wistfully.

Meanwhile, the CDC and NIH have been studying similar programs in a handful of communities using Quidel’s at-home test. Governors have been catching on to the utility of rapid tests too. Last week, the state of Massachusetts bought millions of rapid test kits made by iHealth laboratories. The company’s chief operating officer, Jack Feng, told National Public Radio that the price was higher in the U.S. because of the expense of clinical trials that aren’t required elsewhere.

And since rejecting Bosch’s submissions, the FDA has been coming around to her way of thinking. In March, the agency published a template for tests that would be used serially and sold in packages of two or more, allowing the kind of frequent testing she had advocated for. And last month, it published a new template that lowered the sensitivity standard for single-use over-the-counter tests to 80%.

Bosch had tests a year and a half ago that missed that bar by 1%.

This article was originally published in ProPublica. It has been republished under the Creative Commons license.  ProPublica is a Pulitzer Prize-winning investigative newsroom. Sign up for their newsletter.