For this episode of the Microsamplify Podcast, host Christa Nuber spoke with Remco Koster, PhD, Associate Director of Bioanalytical Science in the mass spectrometry Science Department at PRA Health Sciences. PRA is a contract research organization (CRO) that has participated in thousands of clinical trials around the globe, including trials that have led to the regulatory approval of more than 95 drugs. Dr. Koster discussed how microsampling is used in two bioanalytical labs at PRA — one lab in the Netherlands, and the other in the USA.
Neoteryx: Hello Dr. Koster, and welcome to the Microsamplify Podcast from Neoteryx. We’re excited to learn more about you and your work at PRA Health Sciences.
Dr. Koster: Hi Christa. Thank you for inviting me for this podcast. I’m excited to speak with you about microsampling today.
Neoteryx: Can you tell us a bit about yourself and your background, and what brought you to PRA Health Sciences?
Dr. Koster: Yes, of course. I started my career in 2001 as an LC-MS/MS analyst at Pharma Bio-Research located in Assen, the Netherlands. The company was later acquired by PRA. In 2005, I went to the pharmaceutical and toxicological lab in the University Medical Center Groningen to work as a research and toxicology analyst on the development and validation of analytical methods for drugs and drugs of abuse in matrices like blood, plasma, hair, saliva, dried blood spots (DBS) and volumetric absorptive microsampling (VAMS®) with LC-MS/MS. The daily work also involved trouble shooting, supervising interns and routine analysis of patient and toxicological samples. My research interests and the method development work eventually led to a PhD project, which I worked on in addition to my daily work as a research analyst. In 2015, I finished my PhD research, which was titled “The influence of the sample matrix on LC-MS/MS method development and analytical performance.”
In 2017, I felt ready for a new challenge and I contacted my previous colleagues at PRA Health Sciences. Things moved quickly and I accepted the job of Senior Scientist. In 2019, I accepted my current role of Associate Director of Bioanalytical Science and, as such, I’m responsible for method development of mass spectrometry methods in our laboratory in The Netherlands. During the past years, I was still involved in the implementation of microsampling in the patient setting at the University Medical Center Groningen, and this collaboration yielded some very nice publications. Over the years I authored and co-authored over 35 publications.
Neoteryx: Can you provide us an overview of the services that PRA Health Sciences provides?
Dr. Koster: We are a global healthcare partner where we help to develop life-saving and life-improving drugs with our comprehensive clinical development services. This includes data management, statistical analysis, clinical trial management, medical writing, and regulatory and drug development consulting. PRA has over 17,500 employees worldwide, we have more than 75 offices and are present in over 80 countries.
Since 2000, PRA has participated in approximately 4,000 clinical trials worldwide. In addition, PRA has participated in the pivotal or supportive trials that has led to U.S. Food and Drug Administration (FDA) or international regulatory approval of more than 95 drugs.
We have two laboratories: one in Assen, The Netherlands and one in Lenexa, Kansas, USA. We have the capabilities to outsource bioanalytical studies in China through two of our partners, and this work is managed and monitored by our scientists and project managers in The Netherlands and USA. We have three Phase I clinics: one in Groningen, which is a 15-minute drive from the lab in Assen, and two in North America, in Lenexa and Salt Lake City. Both laboratories have a GMP Quality Control lab for testing of the prepared medication. In Assen we also have an Isotope laboratory. Both labs offer bioanalytical services with the use of various analytical techniques, which include LC-MS/MS, Ligand Binding Assays (LBA) and Flow Cytometry assays. In addition to bioanalysis, we also perform biomarkers analysis at both departments.
The clinical studies that are performed at PRA range from Phase I to Phase IV and the laboratories also support pre-clinical studies.
Neoteryx: It seems your team at PRA Health Sciences is focused primarily on providing analytical services for early drug development. Can you discuss how and why PRA provides these services, with a focus on microsampling techniques?
Dr. Koster: At PRA we believe that behind every sample waiting to be analyzed, there is a patient waiting to be treated. With this mindset, we believe that we should always act in the best interest of the patient. The use of microsampling plays an important role in decreasing the patient burden. The setting in which the samples are taken is also important to consider. Who will perform the sampling? Are the patients neonates or adults?
Although easy and painless sampling is very beneficial for the patient, a high-quality sample is also important for the quality of data. A low-quality sample or a rejected sample is eventually an increased burden for the patient, because a new sample has to be taken, if that’s even possible at all for that time point. While the chosen microsampling technique can provide an easy sampling procedure for the patient and nurses, the technique should also be practical for the laboratory to work with. By continuously assessing new microsampling techniques, the practicality in the laboratory can be assessed before clinical studies are initiated.
Our LC-MS/MS Science team performs all method development of the assays used for sample analysis. The use of microsampling in a clinical study will make it a part of the method development. When developing bioanalytical methods, we aim at ensuring high-quality analytical results. Items like an efficient and robust extraction of the analyte from the dried matrix and analyte stability in the dried matrix need to be investigated before clinical sample collection starts. Encountered issues can influence the choice of which microsampling device is used. For example, if the analyte is difficult to extract from a dried matrix, it might be best to switch to capillary sampling instead.
In many instances, the sponsor will request how PRA can help them in the application of microsampling for their study and valuable information can be derived from early feasibility studies performed in our laboratories. As the global microsampling specialist within PRA, I’m involved in these discussions from an early stage.
Neoteryx: So far we have discussed the benefits of microsampling in the area of drug development. Based on your long experience in the field, do you think microsampling can be beneficial in other areas, such as toxicology screening and wellness screening, for example?
Dr. Koster: One of the advantages of microsampling is that it can be performed at home by self-sampling. This makes it applicable for all kinds of self-monitoring such as wellness screening, which allows an individual to gain more insight in their health status. People should, however, be careful with the results that are generated with home sampling. The reliability and interpretation of the analysis results go hand-in-hand with good sampling. Especially when the analysis results are quantitative. These are important aspects that can affect the reputation of home microsampling.
Microsampling can certainly provide advantages for toxicology screening of abused drugs or drugs of abuse. Some drugs are rapidly metabolized in the body and evidence of drug abuse will be difficult to generate when a blood sample is taken at a later time at a clinical site.
Roadside drug testing is another example where microsampling can provide solutions for the current blood sampling procedures. Currently, in The Netherlands roadside drug testing is performed with a saliva point-of-care device. When the devices test positive for the presence of drugs, a venous whole blood sample has to be taken by a qualified physician within a certain time-frame and the sample has to be stored and transported to the laboratory for confirmation analysis by a cold chain, because of the instability of several drugs at room temperature. Microsampling performed by a trained police officer and omitting the cold chain would enable the authorities to simplify and streamline the process for the confirmation of drug abuse.
Neoteryx: With the COVID-19 crisis, we have seen many changes in the world, including workflows and the way people conduct research, drug trials, and clinical projects. Can you discuss how microsampling might benefit your customers and help them overcome challenges in situations like the coronavirus pandemic?
Neoteryx: The COVID-19 pandemic has created an increase in microsampling applications to be performed. However, a lot of these applications are qualitative or semi-quantitative. For example, to determine if a person has been infected with COVID-19, or what percentage of a population has been infected with COVID-19? At PRA, we mostly use microsampling for quantitative analysis of a new drug compound and this requires high-quality samples and extensive analytical and clinical validation. Microsampling can certainly benefit our sponsors when their clinical trials can be performed from home. And, of course, we try to support this as much as we can.
The analytical experience in our laboratory is extensive, but each compound can behave differently and feasibility should be investigated each time. This can be performed in a time-frame of a few weeks. Changing a clinical study from analyzing liquid plasma samples to dried whole blood samples requires a clinical bridging study to compare the results from both matrices. This requires additional efforts, and such a bridging study should be performed as early as possible in the development process. Rapidly changing to dried blood microsamples for a clinical study during the COVID-19 pandemic is difficult. However, these times make everyone realize that not having the possibility for home microsampling is a vulnerable aspect of performing clinical trials.
Neoteryx: Can you explain from a lab director perspective what you are looking for in a high-quality blood sample for lab analysis, and how the Mitra® microsampling device fulfills that? Perhaps you can explain the problems you encountered with dried blood spot or DBS cards, and other blood sampling techniques, and how the Mitra with VAMS devices helped overcome those previous problems?
Dr. Koster: While a microsampling technique can provide an easy sampling procedure for the patient, the technique should also be practical for the laboratory to work with. With microsampling, there are two ways of generating the sample. Inaccurate volume sampling and accurate volume sampling. With inaccurate volume sampling, by letting a drop of blood fall on the DBS card, the accurate volume is taken by a sub-punch from the DBS in the laboratory. Here the fixed DBS punch area represents a certain blood volume. With this type of sampling, the effect of the blood hematocrit is of influence on the formation of the blood spot area and this can cause biases in the volume and, thus, the analytical results. With accurate volume sampling like the Mitra VAMS device, the blood hematocrit doesn’t affect the sampled blood volume. This decreases the variability of the analytical results.
For both DBS and Mitra VAMS, over- or under-sampling is a potential risk and can affect the sample quality. With DBS, one has to carefully evaluate the sample by looking for sampling errors, like no free fall of the blood drop, double touching of the card, smearing and possible under-sampling by looking at the other side of the DBS card. Over- or under-sampling can still occur with Mitra VAMS tips, but there are fewer variables to evaluate. Under-sampling can be detected when a Mitra VAMS tip still shows white. Oversampling can be detected by observing deformation of the tip by the excess of dried blood. So performing the blood sampling should be easy and fool-proof, and evaluation of the sample quality in the lab should also be easy.
Microsampling techniques that use capillary sampling onto a dried blood spot card or simple DBS sampling require DBS punching equipment in the lab, which may lead to carryover between punched samples. At PRA, DBS is almost never used for our studies, so it wouldn’t make sense to buy expensive automated punching equipment. Manual punching of DBS cards is very laborious and should, thus, be avoided. The devices that make use of capillary sampling onto a dried blood spot card are also more expensive.
At PRA, microsampling studies are mostly not generating the number of samples that would make us consider to automate this process. So an easy manual process for sample handling is favorable. In our workflow, we use the 96-well plates for the extraction of the Mitra VAMS tips. We don’t submerge the complete tips and [pipette] shaft, but we pull the tips from the shafts along the edge of the wells of the 96 well plate. This is an easy procedure, generates a larger extraction surface area of the tips, and allows us to cap the plate during the extraction. So, I believe that the Mitra VAMS can provide high-quality samples in combination with an easy manual laboratory process, which can also be automated when desired.
Neoteryx: What equipment are you using in your lab and/or how much did you have to adjust your lab setup to be compatible with Mitra microsampling technology?
Dr. Koster: At the LC-MS/MS department all samples are, of course, analyzed with LC-MS/MS. This means that the generated extracts need to be compatible with the applied chromatography. Because we apply manual extractions of the Mitra VAMS tips in 96-well plates, we didn’t have to invest in automated processing equipment. Equipment like vortex mixers, sonification equipment and centrifuges are already available in the lab. For Liquid Extractions, we can use an automated TomTec platform, but we’d rather use our horizontal linear shaker, which doesn’t require any programming and also works very well for the extraction of dried microsamples.
Neoteryx: Is there anything you would like to add about what makes your lab unique from other labs in the Netherlands or elsewhere, or to explain anything else about your lab’s capabilities?
Dr. Koster: Our Lab consists of several teams with different analytical techniques and purposes. We also have a Biomarker team that uses a combination of the available analytical techniques and people from the different teams. The advantage of having multiple analytical techniques in different teams all in one building is that equipment, knowledge and techniques are easily shared between teams. For example, the LC-MS/MS team doesn’t have equipment to measure the blood hematocrit, but another team has. Being able to measure the hematocrit is very important for method development of dried whole blood microsampling assays. So I can just walk to the other team with my blood samples for a fast and easy hematocrit determination.
But, ultimately, it’s not the equipment that makes a lab unique, it’s the people working there. The combination of knowledge and the pleasant way of working together is what makes the difference. And the PRA slogan, "Behind every sample waiting to be analyzed, there’s a patient waiting to be treated," always makes us realize what our ultimate goal is.
Neoteryx: Thank you, Dr. Koster, for taking the time to speak with us about how you use microsampling in your lab studies and also about the service capabilities of PRA Health Sciences. We wish you much success with your many projects! And, thank you to our audience for listening to this episode of the Microsamplify Podcast, a partner to The Microsampling Blog from Neoteryx.
PRA Health Sciences, a contract research organization (CRO)