In 1988, the Clearblue lateral-flow rapid pregnancy test hit the shelves. Again, with input from focus groups, the team developed a design that was very easy to use and reliable. Just pee on a stick (the lateral-flow test wick if you’re being scientific) and wait a couple of minutes for the test and control lines to appear. “We were standing astride two worlds.” Davis explained. “The world of serious scientific innovation: from understanding the way the antibodies work to understanding the whole immunology behind it. And yet, getting into the commercial side. It was a combination that gave birth to such a simple and clever technique.”
Lateral-flow tests. Today, they are commonly found in the home. So many of us have used them after the “joy” of swabbing our noses to test for COVID-19 infection. But even before 2020, lateral-flow tests (LFTs) were often used for at-home diagnoses albeit mainly by women of child-bearing age. I’m talking, of course, about at-home pregnancy tests. Because of these tests’ accessibility and ease of use, people may take them for granted. But there was a time, just a few decades ago, when women generally went to the doctor to find out if they were pregnant. Recently, I talked to Professor Paul Davis co-owner of Creonate Manufacturing and one of the inventors of Clearblue, the first lateral-flow test and the first rapid test designed for use at home. We discussed how this LFT came to be and the innovations involved in designing it. He reflected on the lessons he learned and how current test designers can apply these lessons to streamline the development of their own assays. Finally, we talked about the benefits of collaboration in assay design and manufacturing.
Before lateral flow
Before the first version of Clearblue test was released, a variety of awkward home pregnancy tests were on the market. But those tests were difficult to use, less reliable, and needed more time to reach the result. For example, one self test involved collecting urine, mixing it with reagents, and then waiting two hours for a ring of precipitate to form at the bottom of a tiny test tube. The test-kit included a test tube holder with an angled mirror so you could observe the test result without disturbing the tube. Indeed, the test was very sensitive to vibrations and would give a false negative if moved too much or placed near an active washing machine. The kit also had many pieces and was complex to manufacture.
The original Clearblue test that Davis and his team developed improved greatly on the precipitate-based test. It was released in 1985, almost 40 years ago. The test kit instructions were simple. A dipstick with a little vial attached to it was used to collect urine. The dipstick was then incubated successively in three solutions for 10 minutes each. After 30 minutes, the woman removed the dipstick to see the test results. If the end was blue, she was pregnant.
The Clearblue team knew that the end-user of their test was extremely important. Working with Unilever’s marketing experts, they held focus groups to discuss the needs and desires of women who might use the test. They showed the groups prototypes and got their input on the design and use. “It was still fairly clunky, but it was the first pregnancy test to use input from real customers,” said Davis. So, Davis and the team were happy with the first Clearblue test, but they also knew that something better and easier would come along. And they were determined to be the ones who made it.
Three innovation steps to rapid lateral flow
“We wanted to be the people that would displace this early product by something better, and we formed an innovation group,” said Davis. “We would meet quite frequently. Shut up in a room, perhaps all day, with flipcharts all over the wall and ideas of how we might do it. And at the end of each session, we would be paired off to go back to the lab to explore the idea that we had been assigned to.” Out of these sessions came two of three important innovations that would eventually lead to the lateral-flow pregnancy test.
The first of the three innovations actually came before the original Clearblue test was released. Davis and Phillip Porter developed the technology that allows one to use monoclonal antibodies (mAbs) to bind the target hormones and simultaneously bind at different sites. The mAbs could be used to make what are now known as sandwich immunoassays , but without the complication of separation steps.
The second innovation came out of the efforts of the working group. Keith May, Mick Prior, and Ian Richards designed an assay architecture that made the test steps happen automatically and in the correct sequence. Sounds a lot like a lateral-flow test, doesn’t it? It became, in fact, the first patent on a lateral-flow design.
A further important step was covered in a second patent arising from the development of an assay design that delivered optimized performance in the final manufactured product. After all, an assay—particularly one designed for at-home use—isn’t useful unless it can be manufactured at a large scale! The inventors of this design were Davis, May, and Prior.
Proudly presenting “pee on a stick”
The test rapidly became the market leader. Davis showed me photos of the first test, and it looked remarkably similar to many of the tests in use today. Obviously, the design was cutting-edge and robust enough to stand up over time. Today, some pregnancy tests have digital readouts that tell the user in words if they are pregnant or not, but the lateral-flow mechanism inside the test is still basically the same.
Lessons learned
At this point in our conversation, Davis took a step back and reflected on the things he learned while developing Clearblue and during his long career in immunodiagnostics. Obviously, he’s learned a lot and has a brain full of knowledge to share, but what he told me fell into four main categories.
Keep the end user in mind
“Spend time learning the needs and constraints of the intended user,” Davis said. Diagnostic tests intended for use at home need to have easy kit instructions. Tests used in medical settings can be more complex, yet some may still be performed by minimally trained technicians. Tests for use in remote locations may need special handling and storage. Davis emphasized that assay developers need to always think about the end user. An assay can perform beautifully in R&D, but if it doesn’t meet the needs and abilities of the person who will ultimately conduct it, the assay will not be successful.
Stay up to date with technology
“Make sure you understand the technology landscape,” Davis emphasized. “What was going on before? What is known and what can be built on? We built on various different bits of technology, but you need to be very aware of what’s going on.” Tapping into relevant technology and combining different technologies can inspire innovation. Davis showed me a new COVID-19 test (COVI-Go from GADx) that is, believe it or not, even easier than the ones you’ve probably used. Swab, pop the swab in a vial, swish, and turn the container over. The swab breaks the seal of the vial, and everything needed for the test is inside including the lateral-flow test strip!
Davis also described a new in-home LFT system of which he is co-inventor. It gives early warning of debilitating exacerbations of chronic obstructive pulmonary disease (COPD) enabling early pre-emptive medication. This test takes advantage of Bluetooth technology and machine learning to read the results. The test also samples a person’s urine, so the collection device resembles the Clearblue pregnancy test. “It looks and feels very much the same, but we’ve got better antibodies and signal tags. And we’ve got smartphones. So it’s clear that the scope and underlying technology of LFTs has been improving, but we’re still looking for more drastic improvements steps. The future is bright.” Davis is determined to find a way to make this test available to needy patients, but it needs plenty of intercompany cooperation to make it happen.
Know how to navigate regulatory requirements
Regulatory requirements vary in different countries and regions of the world. So, you must understand and conform to the various requirements during test development and manufacture. These regulations can change. For example, a new in-vitro diagnostic (IVD) directive in the European Union became effective in 2022. “The FDA is an absolute minefield,” Davis said. If you aren’t well versed in the regulations, collaborating with someone who is can help you safely cross that minefield.
Prepare for costs, secure backing, and collaborate
“Don’t underestimate the cost of bringing technology to the market,” said Davis with a little groan. “It’s hugely expensive. With the right planning and supported backing, it’s possible to move fast. And we did move fast. Way, way faster than anyone expected.” Naturally, having financial support is a must, but Davis also talked about the importance of support and collaboration with component suppliers and manufacturing organizations.
“Right at the start we had to invent more or less everything ourselves. There were no supply chains and no manufacturing equipment that you could buy. Imagine how much easier it would have been if we were able to collaborate and get those components. Most companies are not in a position to do all of that themselves.” Davis showed me a short video of the first Clearblue manufacturing line where a lot of work was done by hand. The video noted that in six months “an amazing 4 million units have been produced!” At this point, Davis laughed and pointed out that in the COVID-19 pandemic 3 billion LFTs were produced and performed globally through to mid-2022. (Unfortunately, only 0.4% of these tests were performed in low-income regions.)
Davis compared manufacturing a lateral-flow test with one aspect of making a car. Parts are brought in at the right time and in the right order to make the car. “Obviously, a lateral-flow test is not as complicated as that,” explained Davis, “but it’s still true that you need to get your materials in time with the right cost and the right specification. You need to be able to trust that specification. You need to know that when you’re putting everything together, all of the parts that come together are made by people that know what they’re doing and can provide an affordable, relevant service according to strict manufacturing procedures. There’s no room for error.”
Be mindful of manufacturing
Davis touched on the topic of manufacturing a few times. He cautioned assay developers to be careful not only when designing the chemistry behind a test but also when designing the physical testing device itself. “It’s not just what your test looks like,” he said. A device can be handmade and perform well in the lab, but if the manufacturing process is too complicated, you wouldn’t be able to produce enough volume at a reasonable price to make your assay financially successful.
“The manufacturing bit needs the right, full supply chain from the antibodies and nanoparticle labels and all of the essential, hidden ingredients.” Davis emphasized. “You need, if you can get it, an end-to-end commitment [from a collaborator] about what you’re going to do.”
Davis also noted that the COVID-19 pandemic and public health crisis allowed the industry to learn a lot about manufacturing at scale in a short amount of time. While the task was accomplished, Davis felt that it took too long to get the tests right and that there was too much variability from different suppliers. “One of the things the industry needs to be doing now is sorting out how they can be much better prepared, move faster, and understand the way they can get really effective products into the market,” he advised.
No person, company, or lateral-flow test is an island
Davis and I finished our conversation with one final thought about collaboration. He expressed it so well that I’m not even going to try to paraphrase it.
You know, you would be able to achieve so little if you could only ever be one company and not have the support of other companies. I think scientists and technologists these days are so fortunate that we can buy so much of the stuff we need.
The whole infrastructure that we’ve got is something that makes us able to be human beings that cooperate. Our ability to collaborate and cooperate is something that makes human beings as successful as we are. And that’s very true about companies. If you can work with the right companies, you can achieve so much more.
Paul Davis and his colleagues and collaborators made and continue to make a big impact on healthcare and public health. The wide-spread availability of a variety of at-home test kits allow people to manage their own health more effectively.
Collaborate with us during your assay development
About Paul Davis
After six decades of work in scientific research, Paul Davis is now happily retired but still enjoys being a teacher and a mentor. He began his career in 1965 as a lab technician at Unilever. Over the next three decades, Davis was steadily promoted within the company while working on various immunoassay and diagnostics projects. He eventually had the position of Creativity Mentor in which he helped people and teams tap into their own creativity. After leaving Unilever, Davis founded several life-science companies including Mologic (now Global Access Diagnostics), AustinDavis Biologics, and Creonate Manufacturing. He has held visiting professorships at the University of Kent, Warwick University, Cardiff University, and Exeter University.
Clearblue is a trademark of Swiss Precision Diagnostics GmbH
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