For this episode of the Microsamplify Podcast we spoke with two thought leaders in microsampling. Neil Spooner, PhD, C.Chem, FRSC, Senior Editor of the Bioanalysis Journal and Founder and Owner of Spooner Bioanalytical Solutions, Ltd., where he is an independent consultant. Previous to that, Neil spent more than 20 years working in various leadership positions at GlaxoSmithKline (GSK). Also joining the discussion was James Rudge, PhD, the Technical Director at Neoteryx, who also has a background in research science and lab analysis, and is the co-inventor of a microsampling device called the Mitra® microsampler, which is based on volumetric absorptive microsampling, or VAMS® technology.
Neoteryx: Hello Dr. Spooner and Dr. Rudge, and welcome to the Microsamplify Podcast from Neoteryx. Thank you for joining us today!
Drs. Spooner and Rudge: Thank you!
Neoteryx: We’re here to talk about the value of microsampling in healthcare and research science, and I believe the two of you have had some longstanding discussions about how to make microsampling methods better, both for patients and for lab analysis. Can you give us a brief history of your early discussions about improving microsampling technology?
Dr. Spooner: I can’t remember the year our discussions started, but I guess it goes back to the time when I was at GlaxoSmithKline. We were trying to figure out how to better support pediatric clinical trials. There had been some changes in the regulations requiring medicines to be registered for children where appropriate. We were reading about what was going on in neonatal screening. We read about what people like Kevin Bateman were doing at Merck with dried blood spots (DBS), which made us think about that. We investigated that technology and worked with a lot of people that helped us move forward with that.
We made a decision at GSK to move forward with DBS for all our clinical and preclinical programs, where appropriate and where sensitivity worked. Because of the number of added advantages for adult sampling, as well as children sampling—such as being to ship samples at room temperature, better stability, and smaller samples. Also, applying smaller volume sampling to preclinical work became important to us as well, and to a lot of other companies. We created a lot of interest in the industry. However, we realized that while these tools for DBS were really good for certain applications (i.e., neonatal screening, therapeutic drug monitoring), the kind of numbers we needed to generate raised some concerns over the hematocrit (the amount of red blood cells in a volume of blood)—it changes the viscosity, which changes the size of the blood spot. We didn’t have to meter the volume of blood, because we didn’t think we could readily do that in people’s homes or in the clinic. It was just too complicated with the technology at that time to collect an accurate volume of blood.
The idea was that we collected an approximate volume and then got an accurate volume by a sub-punch of the dried blood spot. It turns out that hematocrit changes the viscosity of the blood sample. This means that when you take a fixed-diameter punch, you actually don’t know what volume of blood you’re taking. Plus, there were issues with homogeneity. So, while we were very excited about the benefits, we saw that in order to create the level of data quality we needed for registering drugs, we needed something more. That started us having some conversations. And that is why I started having a conversation with James. I can’t clearly remember where we had [the first conversation], but I think it was a BMSS conference where we started chatting about this.
We discussed the benefits of this technology, but how there were major drawbacks in how we wanted to use it, and that set James’s brilliant mind going to start having ideas.
Dr. Rudge: I also am having difficulty remembering which conference it was, but I distinctly remember you talking about the benefits and disadvantages of dried blood spot analysis for the work that you were doing. I remember thinking about the fact that my father had diabetes—he took microsamples for his blood glucose levels on a microfluid strip—and I thought to myself, wouldn’t it be neat to develop something which has the same value proposition, but could be used [more generically] for compounds? I asked you, “What about this as an idea?” You said, “That’s a great idea! Why don’t you go off and develop it?” I think I came round your lab the next week to borrow some dried blood spot paper to start to develop a few prototypes. There on in, we started to look at ways in which we could lock the volume on those paper prototypes. We started thinking about lab flow as well—we started moving from card-based samplers to pipette-based samplers. We had some good fun in your labs back in the day! It was 2009, I think.
Dr. Spooner: Yes, 2009! Also integral to that was Phil Denniff, who is now retired. Without him and his lab expertise and persistence, we’d have never got there. It needed you cutting things out on your kitchen table, and Phil having the lab skills to work with you to get a prototype that worked—that, regardless of the hematocrit, took a fixed volume of blood. Even before it was a workable solution, we could prove that with these dried blood samples, we could collect an accurate volumetric sample of blood. That was a really big breakthrough.
Neoteryx: Many labs are still using dried blood spot, or DBS cards, microsampling. What are the challenges or limitations with DBS technology/methods and how do you think volumetric absorptive microsampling, or VAMS technology, can help overcome those limitations?
Dr. Rudge: I’d like to mention a paper from Jana Kovatch from the Swiss School of Tropical Medicine, published in 2019. They compared dried blood spot and Mitra for testing 35 children infected with a fluke worm in Ivory Coast. What she mentions in her introduction, really says it all:
“Unfortunately, in non-controlled settings such as rural areas or the tropics, and especially when working with young children, homogenous spots of irregular shape or size can be common, giving rise to unreliable results. Furthermore, the hematocrit is well-known to have an effect on the accurate quantification of analytes from DBS quality...”
This echoes what Neil was saying in response to the previous question.
Dr. Spooner: What I have to say as well, is that DBS for certain applications works perfectly well. It is well-established in many workflows. It’s really where we need this high level of data quality or a new level of simplicity in lab automation for the analysis, and a number of other factors, that brings VAMS to the fore. I just wanted to emphasize that the places where DBS has been used, and is being successfully used today, is still enabling people to make good decisions and giving them the quality of data they need to make those decisions. It’s just that the Mitra with VAMS [technology] allows us to take that quality and simplicity to another level, which today is important and is why it has become a successful technology for so many users out there.
Dr. Rudge: I agree. Dried blood spot has been a transformative technology, for example in the neonatal screening world and monitoring world, and has saved thousands of lives since the 1960s since that technology was developed by Guthrie. We’ve got him to thank for being the pioneer of microsampling, back in the day, and it’s still used today. It has all sorts of applications and is a brilliant technology.
Neoteryx: Thinking about the environment we’re living in today; can you talk about how and why microsampling techniques and remote blood collection methods may become the top choice of most labs in a post-coronavirus world?
Dr. Spooner: In one sense, nothing has changed. The advantages are the same as they were before COVID-19. What’s happened is that a lot of organizations that were looking at adopting these kinds of technologies before, [have now done so]. The pharmaceutical industry, and many other industries, are quite conservative. It is their job to develop high-quality drugs that are safe and efficacious, and changing their workflows is kind of difficult. They’re concentrating on developing a drug, not necessarily on how they perform the clinical trials. So, in a lot of organizations there have been a lot of people who, understandably, find a lot of reasons not to change or to take their time and watch what’s going on.
What has happened now with the coronavirus pandemic is that the positive reasons haven’t changed, but people are no longer wanting to leave their homes. They are not wanting to go into a clinical setting for fear of being infected or infecting someone else. People feel safe in their own homes, or have been told to stay in their own homes. We have seen—when talking to people at contract research organizations and pharmaceutical companies, and companies like yours that develop these kinds of technologies—a big uptick in interest in these kinds of technologies.
Whether it’s for clinical trials or routine sampling for routine healthcare people have realized that people don’t want to go into clinical settings at the moment. Maybe a large proportion of the population will never want to go back to those places. So, if you want to be monitoring the health of those people, or you want to include them in your clinical trial and maintain them in your clinical trial, you have to find another way of working with them and sampling them. Obviously, blood sampling is not the only thing that goes on in a clinical trial, but it is one of the big reasons why people have to go into a clinical center.
I think what was happening anyway has been accelerated. I see it as the silver lining of the very dark cloud that is the COVID-19 pandemic. Some of the reasons not to use this technology have been swept aside, and the reasons to use it are still there. There has been a lot more interest, and I’ve certainly heard reports of project teams in pharmaceutical companies who were a little nervous about looking at the technology for their trial, and they have suddenly said, “I want my trial to go ahead! What can you do for us, and will this work?” And we’re able to give many examples of many groups who, over the last few years, have successfully used these technologies. They have generated high-quality data that has been put to regulators and has been accepted.
Dr. Rudge: I think what the virus pandemic has done is to force people to embrace new technologies across the board, and one of those is teleconferencing. We’re having this discussion over a teleconferencing system—partly because of geography, and partly because of social distancing—which shows that we’re willing to change the way in which we work. The UK may not go back to the way it was in terms of how people were working. More and more people may work from home now, and so the idea of tele-transactions—whether it is telemedicine or the way people communicate—is going to go a lot more virtual. This plays into remote sampling.
Neoteryx: Let’s focus on the advantages of patient-centric microsampling in different industries and scenarios. For example, How do Mitra and VAMS microsampling help the physician who is caring for patients—most of whom may prefer to avoid in-clinic visits in the near and distant future?
Dr. Spooner: To me, the clue is in the name of what we used to call “microsampling,” but now a lot of people are calling “patient-centric sampling.” We need to draw blood samples for many of the tests we do with current technology. The traditional way was putting the analytical scientist at the center. It was all about what volume of blood in what format—wet sample, frozen sample or whole blood plasma, etcetera—would be amenable to the analytical scientist. We didn’t really pay attention to what the patient, subject or consumer thought about that. They just had to go to their doctor’s [office] or elsewhere to have a blood sample drawn, often in large volumes.
The thing is, the world has moved on. Analytical techniques have become more sensitive. Whether it’s for clinical chemistry, pharmacokinetics, or biomarkers, most of the analytical methods need a much smaller volume of blood now. A lot of that large blood sampling in a traditional phlebotomy tube is literally being thrown away. I don’t think we should be doing this, because it’s not very ethical. This [microsampling] technology has now moved the patient to the center.
We’ve had a lot of conversations with doctors and medical scientists, particularly at the CPSA conferences, who are saying, “We don’t necessarily want our patients to have to take time off work or time off school to come to us to then take up our precious time to have a blood sample drawn when they can get high-quality data at home doing it themselves or assisted by someone else. As long as we can still get the same quality data, we don’t need to be doing this piece. We’ve got other things we can be doing to provide healthcare. We’ve heard that message a lot from a lot of clinicians at the CPSA events. This message came across loud and clear.
Dr. Rudge: Another example is that a while back we interviewed Dr. JJ Kim about his “CountonMe” kits that are being used by the NHS for his pediatric transplant patients. This [at-home blood collection kit] was an idea he came up with before the COVID-19 crisis, but since the crisis it has become even more important because his patients are at-risk patients in regard to [potential] complications of the COVID-19 disease. [The kit] allows him to continue performing his blood tests for both the therapeutic drug, but also for the biomarker creatinine, which is really transformative for him. He can actually then calibrate the tests specific to the patient, depending on what the patient needs. I think we’re going to see more examples like this moving forward with patient-centric sampling. As you said, Neil, bringing the patient right to the forefront.
Dr. Spooner: And, potentially, getting more data or better data than we currently have. We’ve got the ability with these technologies, because they’ve been moved closer to the patient, to be able to collect more data points on more analytes and more readily monitor disease, or health, or drugs during drug trials. [This enables us to] get more quality data in a simplified manner that is less intrusive on the patient or subject in a clinical trial. I think it’s got all the makings of being a broad win in terms of the patient, data quality, what the doctor wants to know about their patient so they can help them, and so they can monitor more things more regularly.
Also, I think [microsampling technology] enables us to take a bit more control of our own healthcare, rather than relying on doctors and other healthcare providers to make all our decision. If we’re able to be involved in collecting our own samples, seeing our own data and interacting with our own data, and interacting with our healthcare providers, I think that’s a big democratization of healthcare that enables all of us to take a bit more control of what’s happening with our own healthcare. Whereas I think sometimes, with a lot of people, the way we used to do things or are doing things at the moment, feels like it’s being done to you rather than being done with you. I think that’s a fundamental change that is going to take a little bit of getting used to for everyone.
Neoteryx: With this growing preference for remote blood collection using devices that deliver smaller volume blood samples in a dried format, how do you think analytical labs will adapt their workflows?
Dr. Rudge: From my perspective, I think it really depends on the microsampling device in the lab. Some labs that are routinely running LCMS, ELISAs, and immunoassays will have an easier job of adapting microsampling workflows. A lot of these are based on 96-well processing systems. I think the use of 96-well processing robots will potentially increase as a result as well. Things are going to be difficult when we start looking at some of the routine chemistry analyzers. As Neil mentioned, people are taking armfuls of blood—7 mL of blood in one tube, and often in several tubes—because it depends upon the preservative of the blood for the test that is required. The systems are actually only requiring small amounts of harvested plasma or blood or serum for those assays, but it’s because [these systems] are calibrated to use blood tubes and certain volumes within blood tubes, although actually what they’re taking is a small amount of blood. There is a contradiction there. Getting the labs to change to microsampling is going to be more of a challenge.
I think also it is an opportunity for some of these older tests that are less specific and less sensitive to be supplanted with tests that are going to become increasingly more useful. [This is especially true] considering the fact that medicine is becoming more personalized. We’re realizing that diseases are much more heterogeneic, and specific drugs are required to treat specific sub-classes of disease. What you need, then, are ways to be able to diagnose and then monitor those disease outcomes with the new personalized medicines that have been designed specifically to treat the disease.
The drugs being used these days treat not just the symptoms of a disease, but have become disease modifiers. You have to understand the disease and then design the drugs to modify the disease to bring the patient back to health, and then you need the biomarkers to test. That is where medicine is going, and I think clinical science is going to move towards that. Ironically, because of the sensitivity of instruments such as LCMS, microsampling really plays into that.
Dr. Spooner: Absolutely. And the whole change thing is always difficult because human beings don’t really like change. They like things to stay the way they are. So, in an analytical lab change can be difficult—I’ve seen this myself. It helps if we are able to better connect the analytical lab to the patient so they realize the big picture. In the analytical lab it may now be harder—you’ve got to change your workflow, maybe revalidate some of your methods—and maybe you’re struggling with sensitivity. Overall, if you’re providing a better clinical trial, better quality data, or you’re helping the patient at home, these are big advantages. It helps to point those out to the analytical scientist.
I think it’s also interesting to look at some of the clinical testing laboratories and see that they are actually starting to sell these technologies as a sort of advantage. Some of the big central laboratories are starting to embrace dried blood samples and are then extracting them and reformatting them in a way that is compatible with their existing workflows. Likewise, some of the hospital labs are doing this. A lot of the products that are available on the Internet now for home blood testing or health monitoring sometimes use dried blood samples, which are going into analytical laboratories, hospital laboratories or central laboratories that are used to dealing with large wet blood samples.
These labs have realized that if they adapt, this gives them a new angle on some new workflows, and more profits to be made. After all, most places where these analyses are done are businesses, and that is how they are making their money. If they can find a new way that gives them an angle to sell directly to the consumer, then they are motivated by patient centricity and by making money as well. It’s quite complicated, but we’re seeing progress in a number of places for a number of different reasons.
Neoteryx: What kind of feedback have you received from patients or other end-users with regard to Mitra devices for remote blood collection? Do patients and study volunteers generally find Mitra easy to use at home or out in the field?
Dr. Rudge: By and large, yes. To quote Daniella Hoffman from the Swiss School of Medicine, who is credited with saying, “With the use of VAMS in work such as performing PK studies or therapeutic drug monitoring in low resource regions, the whole analytical pipeline becomes more efficient and solid. Oncological studies that take place in marginalized areas become more feasible.” She goes on to say, later on, “What I like the most about using Mitra is that it’s very patient-friendly. It’s easy and intuitive to handle and does not scare patients away from donating their blood.”
I think that’s quite important, and also plays into pediatric fields as well. Having met patients who actually use a Mitra device, it is incredibly humbling. The thought that the device, which started as a conversation over a beer at a conference over 10 years ago is now impacting real life. Another paper from a focus group [poses the question], “Why haven’t we seen this before?” People really appreciate having this as an option, and obviously the statistics are very much in favor of the finger-prick method vs. [venipuncture] and venous samples. There is quite a bit of data out there to show that. It’s been quite an interesting and humbling experience talking to patients and parents of patients.
Dr. Spooner: I think that is a really good point, James, because the voice of the patient—when you hear it as we have done at the CPSA events—does kind of make the reasons not to do it go away. It speaks louder than anything. [We have heard] the mother of a sick child talk about how blood sampling causes real distress—it can cause family breakups and suicidal thoughts—over what we think of as something as simple, as fundamental, as blood sampling. But when you hear those stories, it really is a big leveler. I think we’ve all experienced watery eyes when we’ve heard those kinds of presentations. We need to hear that voice more often and more loudly, I think, because it really does make a difference.
Dr. Rudge: It grounds you as a scientist to think, This is the reason why we get out of bed. This is the reason we go to work and push things forward. When you see the mother of a sick child give a presentation … and she highlights the particular disease that her child has and the issues associated with it—either with treatment or clinical trials, including having to collect blood, especially when there are collapsed veins or veins that are difficult to puncture because of the disease—it really makes you think, We must push forward as a scientific community.
Neoteryx: What place do remote blood collection methods using Mitra devices and VAMS microsampling technology have in the different phases of drug development, from discovery research to clinical trials?
Dr. Spooner: When we look at discovery, a lot of the work is in vitro, and we’re typically doing some early animal models and studies looking at PK/PD and trying to understand that. There are many approaches to that with small blood sampling. Because we’re not necessarily shipping the samples round the world and taking them to multiple locations, I think some of the advantages of dried blood samples are reduced, unless you want to translate your data throughout the whole of drug development. Maybe the same could be said of toxicology studies using animals. Many people are using microsampling in a variety of studies.
For all the stages of clinical trials, the argument for using a dried blood approach is very strong. I’ve seen a Phase 1 study where you’re in a single clinic where you can train the medical staff to collect different kinds of samples in different ways, so [microsampling] is maybe less of an advantage. But once you get to multisite, multicenter clinical trials the advantages become really huge. I’m not saying that there aren’t advantages in earlier phase studies, but I think the later-phase ones, where you’re able to save money—on room-temperature shipping, stability, home sampling, smaller sampling, pediatrics, sampling in remote areas—the advantages just pile up. The advantages are still there in a Phase 1 study and in preclinical, but I think the arguments are so much stronger in those late-phase studies. That’s my belief, but maybe you have a different opinion James.
Dr. Rudge: In the early days, preclinical was all about the three Rs: reduction, replacement and refinement. That’s also important, that the microsampling does improve the welfare of animals [in preclinical studies]. You’re right when it comes to Phase 1 and Phase 2 [and Phase 3/4] studies. When you’ve got patients who are ill, and sometimes quite desperate to have some kind of treatment for a condition, and then they have to travel to a clinical center for their clinical trial, and if that trial could be brought home and allow them to be run at home that’s got to be better for the welfare of the patient. It’s also better for recruitment and compliance. If you can keep it patient-centric, and run it at home, why wouldn’t you?
Neoteryx: Do you anticipate we’re going to see dramatic changes in these industries we’ve discussed or in any other industries that can utilize microsampling technologies?
Dr. Spooner: I think so. I’ve certainly been keeping my ear to the ground in the last few months since the coronavirus pandemic. There seems to be a major uptick in interest. A lot of contract research organizations are saying they are getting a lot of clients knocking at their door saying, “Can you do this? Can you help us with this?” So [changes are] starting to happen. The more we understand these technologies, and the more people get exposed to them and understand what they are and what can be done, the more they will get applied to places we’ve not even thought about. Whether it be in sports science, drug testing in sports, nutrition, workplace drug testing, there are many applications, some of which may not exist at the moment. People are wanting to monitor their own health as well. I think there are a number of places where microsampling is starting to grow, and James will be starting to see the technology that he was involved in inventing popping up in all sorts of places that he didn’t think about. People won’t even know who he is anymore, and the role he played in developing that Mitra device they are holding in their hands—and that’s a good outcome.
Dr. Rudge: As I’ve mentioned before, Neil, when I’m at conferences and I walk past two scientists having a discussion about Mitra and VAMS, it’s quite a humbling experience. You’ve covered the possibilities, Neil, but I would add that there are opportunities for roadside testing by police for drugs as well. Especially if there was an agent that someone’s taken, but it gets rapidly metabolized, there may be an opportunity to capture that.
Dr. Spooner: We’re seeing new things around the current pandemic. I know from labs that have contacted me that have antibody tests, that are wanting to do them in the home setting, and have been contacting companies such as yours to see if they can marry up their technology with your technology. They want to see if they can enable blood testing for SARS-CoV-2 antibodies in the home.
We’re seeing all these issues with the virus testing and the antibody testing. People are just not able to get to the testing centers. If we can bring the testing center to the people, that’s got to be good all around the globe, where they may not have the same kind of infrastructure we’re used to. If these high quality samples can still be collected, and we can get information to control this pandemic, it’s got to be a good thing.
Dr. Rudge: I completely agree. We’ve certainly seen great interest in antibody testing, and also in potential biomarkers for tracking disease, and in some of the inflammation biomarkers. There’s a big interest in that at the moment as well.
Neoteryx: Thank you Dr. Spooner & Dr. Rudge for taking the time to share your insights with us! And thank you to our audience for listening to this episode of the Microsamplify Podcast, a partner to The Microsampling Blog from Neoteryx.
Dr. Neil Spooner, Spooner Bioanalytical Solutions, Ltd.