Dr. Andrew Brooks of RUCDR Infinite Biologics holds up a saliva sample.
The patient tilts back her head and winces as the long swab stick pushes six inches up her nose. The tip twirls around uncomfortably before it's withdrawn.
"Our saliva test can detect the virus in asymptomatic and pre-symptomatic cases."
A gloved and gowned healthcare worker wearing a face shield and mask tells the patient that she will learn whether she is positive for COVID-19 as soon as the lab can process her test.
This is the typical unpleasant scenario for getting a coronavirus test. But times are rapidly changing: Today, for the first time, the U.S. Food and Drug Administration cleared one company to sell saliva collection kits for individuals to use at home.
Scientists at the startup venture, RUCDR Infinite Biologics at Rutgers University in New Jersey, say that saliva testing offers an easier, more useful alternative to the standard nasal swab.
"Our saliva test can detect the virus in asymptomatic and pre-symptomatic cases," said Dr. Andrew Brooks, chief operating officer at RUCDR.
Another venture, Darwin BioSciences in Colorado, has separately developed an innovative method of testing saliva for the coronavirus that causes COVID-19.
Saliva testing can allow earlier detection to identify people who may not know they are contagious, say scientists at both companies. In addition, because patients spit into a tube or cup, saliva testing is safer for healthcare workers than taking swabs. This frees up scarce personal protective equipment (PPE) for use elsewhere. Nasal swabs themselves have been in scarce supply.
Saliva testing, if it becomes widespread, potentially could mean opening society sooner. The more ubiquitous testing becomes across the population, experts say, the more feasible it becomes for public health officials to trace and isolate contacts, especially of asymptomatic cases. Testing early and often will be essential to containing emerging hot spots before a vast outbreak can take root.
Darwin Biosceiences is preparing to seek an FDA Emergency Use Authorization (EUA) this month for its patented "CoVScreen" testing system, which potentially could be available to labs nationally by mid-summer.
Meanwhile, Infinite Biologics will now begin selling kits to consumers for home collection, upon order by a physician. The FDA said that the company's saliva test was as accurate as the nasal swab method used by health care professionals. An FDA summary documenting the company's data reported: "There was 100% positive and negative agreement between the results obtained from testing of saliva and those obtained from nasopharyngeal and oropharyngeal swabs."
The greatest scientific advantage, said Dr. Brooks, is that nasal and oral swabs only collect the surface area where the swab goes, which may not be the place with most viral load. In contrast, the virus occurs throughout a saliva sample, so the test is more trustworthy.
The lab at Rutgers can process 20,000 tests a day, with a 48-hour turnaround. They have 75,000 tests ready to ship now.
The Leap: Detecting Sickness Before You Feel It
"We wanted to create a device that could detect infections before symptoms appeared," explained Nicholas Meyerson, co-founder and CEO of Darwin.
For more than 300 years, he said, "the thermometer was the gold standard for detecting disease because we thought the first sign of illness was a fever. This COVID-19 pandemic has proven that not all pathogens cause a fever. You can be highly contagious without knowing it."
"The question is whether we can scale up fast enough to meet the need. I believe saliva testing can help."
Therefore, Meyerson and co-founder Sara Sawyer from the University of Colorado began to identify RNA biomarkers that can sense when a pathogen first enters a molecule and "sets off alarms." They focused on the nucleic acids concentrated in saliva as the best and easiest place to collect samples for testing.
"The isothermal reaction in saliva takes place at body or room temperature," he said, "so there's no need for complicated testing machinery. The chemical reaction can be read out on a paper strip, like a pregnancy test -- two stripes if you're sick, and one stripe if you're okay."
Before the pandemic, limited but successful human trials were already underway at CU in Boulder and at the CU Anschutz Medical Campus east of Denver. "This was our proof of concept," he said.
Darwin was founded in March and has secured enough venture capital to concentrate protype development on detecting the virus causing COVID-19. So far, said Meyerson, "Everything works."
A small double-blind test of 30 samples at CU produced 100 percent accuracy. "I'm not sure if that will hold true as we go into clinical trials," he said, "but I'm confident we will satisfy all the requirements for at least 95 percent clinical validation."
The specific "CoVStick" test strips will roll out soon, he said: "We hope before the second wave of the pandemic hits."
The broader saliva test-strip product from Darwin, "SickStick," is still one to two years away from deployment by the military and introduction into the consumer drugstore market for home use, said Meyerson. It will affordably and quickly detect a range of viral and bacterial infections.
An illustration of the "CoVStick."
(Darwin Biosciences)
A Potential Game Changer
Society needs widespread testing daily, said George Church, founding core faculty of the Wyss Institute for Biologically Inspired Engineering at Harvard University. Speaking at an online SynBioBeta webinar in April, he urged developing stockpiles of testing kits for home use.
As for any potential of false positives, Church said a much bigger risk is not having enough tests.
"Saliva testing is going to speed up the timeline for opening society a lot," said Meyerson. "People need to self-collect samples at home. A lot more people are going to be willing to spit into a tube than to push a swab six inches up their own nose."
Brooks, of Rutgers, addressed the big picture. "It's critical that we open society as soon as possible to minimize the economic impact of the pandemic. Testing is the surest and safest path. The question is whether we can scale up fast enough to meet the need. I believe saliva testing can help."
The U.S. population is becoming more diverse, but clinical trials don't reflect that, experts say. Some are focusing on recruiting minorities to participate in research.
While racial and ethnic minority groups represent almost half of the U.S. population, the lack of diversity in clinical trials poses serious challenges. Limited awareness and access impede equitable representation, which is necessary to prove the safety and effectiveness of medical interventions across different groups.
A Yale University study on clinical trial diversity published last year in BMJ Medicine found that while 81 percent of trials testing the new cancer drugs approved by the U.S. Food and Drug Administration between 2012 and 2017 included women, only 23 percent included older adults and 5 percent fairly included racial and ethnic minorities. “It’s both a public health and social justice issue,” said Jennifer E. Miller, an associate professor of medicine at Yale School of Medicine. “We need to know how medicines and vaccines work for all clinically distinct groups, not just healthy young White males.” A recent JAMA Oncology editorial stresses out the need for legislation that would require diversity action plans for certain types of trials.
Ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health.--FDA Commissioner Robert M. Califf.
But change is on the horizon. Last April, the FDA issued a new draft guidance encouraging industry to find ways to revamp recruitment into clinical trials. The announcement, which expanded on previous efforts, called for including more participants from underrepresented racial and ethnic segments of the population.
“The U.S. population has become increasingly diverse, and ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health,” FDA commissioner Robert M. Califf, a physician, said in a statement. “Going forward, achieving greater diversity will be a key focus throughout the FDA to facilitate the development of better treatments and better ways to fight diseases that often disproportionately impact diverse communities. This guidance also further demonstrates how we support the Administration’s Cancer Moonshot goal of addressing inequities in cancer care, helping to ensure that every community in America has access to cutting-edge cancer diagnostics, therapeutics and clinical trials.”
Lola Fashoyin-Aje, associate director for Science and Policy to Address Disparities in the Oncology Center of Excellence at the FDA, said that the agency “has long held the view that clinical trial participants should reflect the clinical and demographic characteristics of the patients who will ultimately receive the drug once approved.” However, “numerous studies over many decades” have measured the extent of underrepresentation. One FDA analysis found that the proportion of White patients enrolled in U.S. clinical trials (88 percent) is much higher than their numbers in country's population. Meanwhile, the enrollment of African American and Native Hawaiian/American Indian and Alaskan Native patients is below their national numbers.
The FDA’s guidance is accelerating researchers’ efforts to be more inclusive of diverse groups in clinical trials, said Joyce Sackey, a clinical professor of medicine and associate dean at Stanford School of Medicine. Underrepresentation is “a huge issue,” she noted. Sackey is focusing on this in her role as the inaugural chief equity, diversity and inclusion officer at Stanford Medicine, which encompasses the medical school and two hospitals.
Until the early 1990s, Sackey pointed out, clinical trials were based on research that mainly included men, as investigators were concerned that women could become pregnant, which would affect the results. This has led to some unfortunate consequences, such as indications and dosages for drugs that cause more side effects in women due to biological differences. “We’ve made some progress in including women, but we have a long way to go in including people of different ethnic and racial groups,” she said.
A new mural outside Guadalupe Centers Middle School in Kansas City, Missouri, advocates for increasing diversity in clinical trials. Kim Jones, 51-year-old African American breast cancer survivor, is second on the left.
Artwork by Vania Soto. Photo by Megan Peters.
Among racial and ethnic minorities, distrust of clinical trials is deeply rooted in a history of medical racism. A prime example is the Tuskegee Study, a syphilis research experiment that started in 1932 and spanned 40 years, involving hundreds of Black men with low incomes without their informed consent. They were lured with inducements of free meals, health care and burial stipends to participate in the study undertaken by the U.S. Public Health Service and the Tuskegee Institute in Alabama.
By 1947, scientists had figured out that they could provide penicillin to help patients with syphilis, but leaders of the Tuskegee research failed to offer penicillin to their participants throughout the rest of the study, which lasted until 1972.
Opeyemi Olabisi, an assistant professor of medicine at Duke University Medical Center, aims to increase the participation of African Americans in clinical research. As a nephrologist and researcher, he is the principal investigator of a clinical trial focusing on the high rate of kidney disease fueled by two genetic variants of the apolipoprotein L1 (APOL1) gene in people of recent African ancestry. Individuals of this background are four times more likely to develop kidney failure than European Americans, with these two variants accounting for much of the excess risk, Olabisi noted.
The trial is part of an initiative, CARE and JUSTICE for APOL1-Mediated Kidney Disease, through which Olabisi hopes to diversify study participants. “We seek ways to engage African Americans by meeting folks in the community, providing accessible information and addressing structural hindrances that prevent them from participating in clinical trials,” Olabisi said. The researchers go to churches and community organizations to enroll people who do not visit academic medical centers, which typically lead clinical trials. Since last fall, the initiative has screened more than 250 African Americans in North Carolina for the genetic variants, he said.
Other key efforts are underway. “Breaking down barriers, including addressing access, awareness, discrimination and racism, and workforce diversity, are pivotal to increasing clinical trial participation in racial and ethnic minority groups,” said Joshua J. Joseph, assistant professor of medicine at the Ohio State University Wexner Medical Center. Along with the university’s colleges of medicine and nursing, researchers at the medical center partnered with the African American Male Wellness Agency, Genentech and Pfizer to host webinars soliciting solutions from almost 450 community members, civic representatives, health care providers, government organizations and biotechnology professionals in 25 states and five countries.
Their findings, published in February in the journal PLOS One, suggested that including incentives or compensation as part of the research budget at the institutional level may help resolve some issues that hinder racial and ethnic minorities from participating in clinical trials. Compared to other groups, more Blacks and Hispanics have jobs in service, production and transportation, the authors note. It can be difficult to get paid leave in these sectors, so employees often can’t join clinical trials during regular business hours. If more leaders of trials offer money for participating, that could make a difference.
Obstacles include geographic access, language and other communications issues, limited awareness of research options, cost and lack of trust.
Christopher Corsico, senior vice president of development at GSK, formerly GlaxoSmithKline, said the pharmaceutical company conducted a 17-year retrospective study on U.S. clinical trial diversity. “We are using epidemiology and patients most impacted by a particular disease as the foundation for all our enrollment guidance, including study diversity plans,” Corsico said. “We are also sharing our results and ideas across the pharmaceutical industry.”
Judy Sewards, vice president and head of clinical trial experience at Pfizer’s headquarters in New York, said the company has committed to achieving racially and ethnically diverse participation at or above U.S. census or disease prevalence levels (as appropriate) in all trials. “Today, barriers to clinical trial participation persist,” Sewards said. She noted that these obstacles include geographic access, language and other communications issues, limited awareness of research options, cost and lack of trust. “Addressing these challenges takes a village. All stakeholders must come together and work collaboratively to increase diversity in clinical trials.”
It takes a village indeed. Hope Krebill, executive director of the Masonic Cancer Alliance, the outreach network of the University of Kansas Cancer Center in Kansas City, which commissioned the mural, understood that well. So her team actively worked with their metaphorical “village.” “We partnered with the community to understand their concerns, knowledge and attitudes toward clinical trials and research,” said Krebill. “With that information, we created a clinical trials video and a social media campaign, and finally, the mural to encourage people to consider clinical trials as an option for care.”
Besides its encouraging imagery, the mural will also be informational. It will include a QR code that viewers can scan to find relevant clinical trials in their location, said Vania Soto, a Mexican artist who completed the rendition in late February. “I’m so honored to paint people that are survivors and are living proof that clinical trials worked for them,” she said.
Jones, the cancer survivor depicted in the mural, hopes the image will prompt people to feel more open to partaking in clinical trials. “Hopefully, it will encourage people to inquire about what they can do — how they can participate,” she said.