Patient Centric Blood Sampling and Quantitative Analysis
Description
Authoritative resource providing a complete overview of patient centric blood sampling, as well as its benefits and challenges
Patient Centric Blood Sampling and Quantitative Analysis focuses on the growing interest in alternative means to standard phlebotomy and analytical workflows for the collection and analysis of high-quality human biological samples for the quantitative determination of circulating drugs, their metabolites, and endogenous substances for clinical trials, routine healthcare and neonatal screening. The book clearly explains the benefits and constraints of having patients collect small volumes of blood in locations outside of a clinic (e.g at home), including: patient convenience; less invasive procedures; increased frequency of sampling; applicability to collecting samples from the young, elderly, and those in remote locations; greater frequency; and lower cost per sample. Readers will learn about approaches for successfully implementing patient centric sampling workflows in a number of scenarios, including the clinical setting and in the analytical laboratory.
Edited by four recognized experts in this field, with additional specialists in the discipline enlisted to write the component chapters, enabling greater depth and detail to be added and further raising the scientific standing of the publication, Patient Centric Blood Sampling and Quantitative Analysis includes information on:
* Basics of patient centric blood sampling and techniques and approaches that are available and in development for the collection and analysis of the samples
* Science behind patient centric blood sampling and its implications regarding human healthcare and wellbeing
* Application areas of patient centric sampling, including drug development, clinical chemistry/pathology, therapeutic drug monitoring, and more
* Practical approaches to successful implementation for existing and developing purposes and workflows, and case studies to support implementation within an organization
Giving the reader a broad understanding of what patient centric sampling is and where it might be applied for existing and potential future areas, Patient Centric Blood Sampling and Quantitative Analysis is an essential resource on the subject for many different types of laboratories, areas of clinical research and healthcare, including those in pharmaceutical, clinical, and research functions.
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Persons
Neil Spooner, Ph.D., C.Chem., F.R.S.C., is the Founder of Spooner Bioanalytical Solutions and the Patient Centric Sampling Interest Group (PCSIG) where he champions the implementation of patient centric sampling approaches. Dr Spooner is also the Editor In Chief of Bioanalysis Journal and is a Senior Visiting Research Fellow at the University of Hertfordshire, UK.
Emily Ehrenfeld is President of New Objective, Inc, an industry leader in high performance nano/microflow technologies.
Joe Siple is Director, Corporate Relations for New Objective, Inc., an industry leader in high performance nano/microflow technologies.
Mike S. Lee, PhD, is the founder of the Annual Symposium on Clinical and Pharmaceutical Solutions and Analysis (CPSA) and is the CEO of New Objective, Inc, an industry leader in high performance nano/microflow technologies.
Content
List of Contributors xiii
Foreword xvii
Preface xix
1 Patient Centric Healthcare - What's Stopping Us? 1
Jenny Royle and Rachel Jones
1.1 The Evolution of Future Health Systems 1
1.2 Exploring the Barriers to Home Sampling 3
1.2.1 Barrier One-The Discord Between Innovation and Practice 4
1.2.2 Barrier Two-Ethical and Operational Considerations 5
1.2.3 Barrier Three-Where Does the Liability Sit? 7
1.2.4 Barrier Four-Addressing the Technology Challenge 8
1.2.5 Barrier Five-The Human Touch 9
1.2.6 Barrier Six-Trust in Data Security 10
1.2.7 Barrier 7-Adherence to Service Change 11
1.3 Conclusion: The Changing Role of Home Sampling 12
References 13
2 Tips for Successful Quantitative Assay Development Using Mitra Blood Sampling with Volumetric Absorptive Microsampling 17
James Rudge
2.1 What is Volumetric Absorptive Microsampling? 17
2.2 Tip 1-Ensure the Use of a Correct Sampling Procedure to Prevent Volume-Related Biases 18
2.3 Tip 2-Working with Wet Whole Blood 19
2.3.1 Is Your Choice of Assay Biologically Relevant in Blood? 19
2.3.2 Working with Blood as a Matrix 20
2.3.3 Allowing Analytes to Equilibrate Ex Vivo 21
2.3.4 Bridging Between Venous Capillary Blood and the Role of Anticoagulants 22
2.4 Tip 3-Working with Dried Whole Blood 24
2.4.1 Dried Blood Spot Cards 24
2.4.2 Volumetric Hematocrit Bias-Blood Viscosity 25
2.4.3 Dried Blood is a Complicated Matrix 26
2.4.4 Working with "Aged" Blood 26
2.4.5 Temporal Extraction Bias or Degradation? 27
2.5 Tip 4-Optimizing Extraction Efficiencies from VAMS 29
2.5.1 Measuring Percentage Recovery from Mitra Samplers 30
2.5.2 Extraction Conditions-Where to Start 31
2.5.2.1 Consulting the Literature and Matching Physicochemical Properties 31
2.5.2.2 Adapting Published DBS Methods 32
2.5.2.3 Converting from a Wet (Whole Blood or Plasma) Method 32
2.5.2.4 Starting from a Blank Canvas-What to Consider? 33
2.5.2.5 Choice of Matrix 35
2.5.3 Aqueous Extraction Conditions 36
2.5.4 Organic Extraction Conditions 37
2.5.5 Generic Extraction Conditions 39
2.6 Conclusions 40
References 41
3 Preanalytical Considerations for Implementation of Microsampling Solutions 49
Bradley B. Collier, Peyton K. Miesse, and Russell P. Grant
3.1 Introduction 49
3.2 Sample Matrices 50
3.2.1 Venous Sample 51
3.2.2 Capillary Blood 54
3.2.3 Material Selection 62
3.2.4 Dried Samples 62
3.2.5 Conclusions 63
3.3 Alternate Sample Acceptance Criteria 63
3.4 Collection 65
3.4.1 Device and Kit Components 66
3.4.2 Training and Preparation 67
3.4.3 Wound Generation 68
3.4.4 Collecting Sample 70
3.4.5 Post Collection Processing 72
3.4.6 Conclusions 72
3.5 Transportation and Sample Stability 73
3.5.1 Specimen Matrix and Separation 73
3.5.2 Storage Condition 74
3.5.3 Measurement Technique 77
3.5.4 Hematocrit Effects 79
3.5.5 Conclusions 79
3.6 Preanalytical Processing 80
3.6.1 Separation of Plasma and Serum 80
3.6.2 Sample Dilution 81
3.6.3 Conclusions 82
3.7 Overall Conclusions 82
References 83
4 Collection and Bioanalysis of Quantitative Microsamples: Technological Innovations and Practical Implications 93
Regina V. Oliveira, Marc Yves Chalom, and Carlos Roberto V. Kiffer
4.1 Introduction 93
4.2 Practical Implications in Clinical Settings 94
4.2.1 Clinical Development 95
4.2.2 Clinical Analyses 96
4.3 Microsampling Devices-A Patient-Centered Approach 99
4.3.1 Collection Devices for Microsampling Analysis 99
4.3.1.1 Blood Sampling Techniques 102
4.3.1.2 Other Biological Matrices 124
4.4 New Development Areas 124
4.4.1 Automated Sample Collectors 124
4.4.2 Microfluidic Point-of-Care Devices 127
4.5 Summary of Currently Available Patient Centric Sampling Technologies 127
4.6 Microsampling Analysis by LC-MS-Analytical Considerations 127
4.6.1 Basic Principles of Liquid Chromatography (LC) and Mass Spectrometry (MS) for Bioanalysis of Microsamples 128
4.6.1.1 Microspray Ionization Sources 129
4.6.1.2 Microflow Liquid Chromatography 131
4.6.1.3 Microchip-Based LC 138
4.7 Conclusions 138
References 140
5 Automation in Microsampling: At Your Fingertips? 153
Sigrid Deprez, Liesl Heughebaert, Nick Verougstraete, Veronique Stove, Alain G. Verstraete, and Christophe P. Stove
5.1 Introduction 153
5.1.1 Identifying the Current Bottlenecks for Routine Implementation of Microsampling in Clinical Practice 153
5.1.2 The Importance of Analytical Automation for Different Application Fields 157
5.2 Automation of Dried Blood Microsampling Analysis Coupled to (LC-) MS/MS: What's Available? 159
5.2.1 Amenability of DBS Samples for Automation 159
5.2.2 Commercially Available Automated DBS Extraction Instruments 162
5.2.2.1 Automated Extraction of DBS: Workflow 162
5.2.2.2 Extraction Process 163
5.2.2.3 Extract Processing Strategy 164
5.2.2.4 Internal Standard Application 165
5.2.3 Points of Attention During Method Validation 166
5.2.3.1 Matrix Effects and Recovery 166
5.2.3.2 The Hct Effect 168
5.2.3.3 Calibration Curve and Dilution Integrity 169
5.2.4 Cross-Validation of Automated DBS Procedures 170
5.2.5 Current Applications of Automated Online DBS Extraction 173
5.2.6 Approaches for Automating Analysis with Other Microsampling Devices 181
5.2.7 Alternative Approaches for the Analysis of DBS Samples 183
5.2.7.1 Direct Analysis of DBS 183
5.2.7.2 Coupling DBS Analysis to Automated Immuno-Analyzers 184
5.3 Integration Into a Clinical Laboratory 185
5.3.1 Requirements, Challenges, and Advantages of Implementation 185
5.3.2 Cost-Effectiveness of Implementation of (Automated) DBS Analysis 187
5.4 Conclusions and Future Perspectives 192
Acknowledgments 192
References 193
6 Over 50 Years of Population-Based Dried Blood Spot Sampling of Newborns; Assuring Quality Testing and Lessons Learned 205
Amy M. Gaviglio, Kristina Mercer, Konstantinos Petritis, Carla D. Cuthbert, and Suzanne K. Cordovado
6.1 Overview of Population-Based Newborn Screening 205
6.2 Public Perceptions of NBS 208
6.3 Characteristics of the DBS Matrix and Its Utility in NBS 209
6.3.1 Recovery of Biochemical and Molecular Analytes from DBS for NBS 210
6.3.2 Evaluation of Lot-to-Lot Variability in NBS Collection Devices 211
6.3.3 Effect of Hematocrit on DBS Homogeneity, Data Analysis, and Results 212
6.3.4 DBS Specimen Collection Transport and Safe Handling 213
6.3.5 DBS Analyte Stability and Storage 216
6.3.6 Known Interferences with DBS use for NBS 221
6.3.7 History of NSQAP-40 Years of Quality Assurance 222
6.4 Methods Used in NBS 232
6.4.1 Origins of NBS and Expansion of Biochemical Testing 232
6.4.2 Origins of Molecular DBS Testing and Expansion in NBS 238
6.4.3 How the Expansion of Genomics may Impact NBS 241
6.4.4 Expansion of DBS Utility, Including Direct Patient Use 244
6.5 Conclusion 245
Acknowledgments 246
Conflicts of Interest 246
References 246
7 Considerations for Implementation of Microsampling in Pediatric Clinical Research and Patient Care 263
Ganesh S. Moorthy, Christina Vedar, and Athena F. Zuppa
7.1 Introduction 263
7.2 Considerations for Implementation 264
7.2.1 Benefits 264
7.2.1.1 Clinical Research 266
7.2.1.2 Clinical Care 267
7.2.2 Challenges 268
7.2.2.1 Clinical Research 269
7.2.2.2 Clinical Care 270
7.2.3 Laboratory Challenges and Considerations 271
7.2.4 Survey Results on Feasibility 273
7.3 Conclusion 274
References 274
8 Simplification of Home Urine Sampling for Measurement of 2,8-Dihydroxyadenine in Patients with Adenine Phosphoribosyltransferase Deficiency 277
Unnur A. Thorsteinsdottir, Hrafnhildur L. Runolfsdottir, Vidar O. Edvardsson, Runolfur Palsson, and Margret Thorsteinsdottir
8.1 Introduction 277
8.1.1 Adenine Phosphoribosyltransferase Deficiency 278
8.1.2 Diagnosis of Adenine Phosphoribosyltransferase Deficiency 280
8.2 Methods 281
8.2.1 Sample Collection 281
8.2.2 Preparation of Urine Samples for Analysis 281
8.2.3 The UPLC-MS/MS Urinary 2,8-Dihydroxyadenine Assay 282
8.3 Results 283
8.3.1 Assay Development and Optimization 283
8.3.2 Comparison of First-Morning Void Urine Specimens and 24-hr Urine Collections for Assessment of 2,8-Dihydroxyadenine Excretion 288
8.4 Discussion 290
8.5 Conclusions and Future Directions 291
References 292
9 Utilization of Patient Centric Sampling in Clinical Blood Sample Collection and Protein Biomarker Analysis 297
Jinming Xing, Joseph Loureiro, Dmitri Mikhailov, and Arkady I. Gusev
9.1 Introduction 297
9.1.1 Challenges with the Current Clinical Trial Model 297
9.1.2 Clinical Trial Conduct Faced Unprecedented Challenges Brought by Covid-19 298
9.2 Current Patient Centric Sampling Landscape 299
9.3 Clinical Proteome Profiling Technologies for Testing Patient Centric Microsampling Devices 300
9.3.1 Biomarker and Profiling Can Be Used to Benchmark Patient Centric Sampling Technologies 300
9.3.2 Orthogonal Analysis Cultivates Confidence for Biomarker Test with Patient Centric Sampling 302
9.4 Clinical Sample Collection with Tap Device: A Clinical Case Study 303
9.4.1 Clinical Study with TAP Device 303
9.4.2 User Experience, TAP Device Performance, and Sample Hemolysis 306
9.4.3 SomaScan Blood Proteome Profiling Landscape 308
9.4.4 Orthogonal Confirmation Provided by Quantitative Immunoassay 313
9.4.5 Extending Protein Biomarkers Tested by Quantitative Immunoassay Beyond the Zone of Highest Concordance (Negative Controls) 314
9.5 Discussion 318
9.5.1 Utility of Patient Centric Sampling for Clinical Proteome Sample Collection 318
9.5.2 Considerations for Patient Centric Sampling Implementation in Clinical Trials 320
9.5.3 Future Outlook for Patient Centric Sampling 322
Acknowledgements 323
References 323
10 Enabling Patient Centric Sampling Through Partnership: A Case Study 327
Christopher Bailey, Cecilia Arfvidsson, Stephanie Cape, Paul Severin, Silvia Alonso Rodriguez, Robert Nelson, and Catherine E. Albrecht
10.1 Introduction 327
10.1.1 The Partnership 327
10.1.2 AstraZeneca's Evolving PCS Approach 328
10.1.3 Why Change? 328
10.1.4 Patient Choice 329
10.1.5 The Challenges-Why Isn't PCS Already the Norm? 329
10.2 Pre-Study Considerations 331
10.2.1 Early Engagement 331
10.2.2 Feasibility Assessment 332
10.3 The Case Study 332
10.3.1 Background 332
10.3.2 Scientific Considerations 335
10.3.3 Regulatory Agency Expectations Bridging 338
10.3.4 Study Operations Considerations 338
10.3.5 Route of Drug Administration and Potential for Sample Contamination 340
10.3.6 Sample Handling 341
10.3.7 Training and Patient Recruitment Challenges 342
10.3.8 Other Logistical, Data Protection, and Compliance Considerations 342
10.3.9 Study Participant Engagement 343
10.4 Summary 344
References 347
11 Perspectives on Adopting Patient Centric Sampling for Pediatric Trials 351
Enaksha Wickremsinhe
11.1 Overview and Why 351
11.1.1 Regulations and Legislation 351
11.1.2 Who are Pediatric Patients? 352
11.2 Challenges and Current Status 353
11.2.1 Conducting Pediatric Studies 353
11.2.2 Ethics, Consent, and Assent 353
11.2.3 Patient/Parent Burden 354
11.2.4 Blood Sampling 354
11.2.5 Blood Volume Limits 355
11.3 Solutions: How Do We Get This Done 356
11.3.1 Microsampling 356
11.3.2 Patient Centric Sampling 357
11.3.3 Pediatric PCS Devices/Techniques 358
11.3.4 COVID-19 Era 359
11.3.5 Training 359
11.4 Summary 359
References 360
Index 363
1
Patient Centric Healthcare - What's Stopping Us?
Jenny Royle1 and Rachel Jones2
1 MediPaCe Limited, London, UK
2 Cheshire, UK
1.1 The Evolution of Future Health Systems
The primary aim of healthcare systems around the globe is to improve the well-being of populations, with the World Health Organization defining health as "A state of complete physical, mental and social well-being and not merely the absence of disease or infirmity" (World Health Organisation, 2020). Healthcare is not merely treatments for diseases, it is instead a way to support people to achieve the highest attainable mental and physical and social well-being for themselves. But traditional healthcare systems are not set up in this way, and rather than focusing on integrating all the holistic elements required for promotion of health in an individual, they are orientated toward the treatment of disease and malaise after things have already deteriorated in a person's well-being.
The difference between absence of disease and total well-being is subtle but fundamental. Supporting well-being involves encouraging people to live a healthy lifestyle (both physically and mentally) and providing the tools, systems, and education for each person to aim for the best possible version of themselves often via self-care principles-whether or not they are sick at the current time.
Other factors that have further impacted the tension between the treatment versus a self-care model of health have emerged during the COVID-19 pandemic during 2020, which forced upon us innovations and technologies that were once confined to pilot status. These were mobilized during the 2020 pandemic out of necessity in order to meet the restriction in face-to-face services required to prevent transmission of the virus between people. Many of these rapid accelerations, particularly in relation to telehealth visits and remote monitoring, are here to stay because, once pushed to try a new approach, it has been found to be efficient and a positive experience for many (Jones et al., 2020; Norman et al., 2020; Wosik et al., 2020). An area that is a fundamental component of this wave of change is the process of microsampling at home.
For the uninitiated, microsampling involves the taking of small droplet amounts of body fluid-blood or saliva as examples-in the comfort of a person's home. The samples themselves are taken by the patient or with assistance from a caregiver and are then stored and packaged as directed (for example by drying on a specialized sample tip or card and sealing into the envelope provided). These are then either posted or collected and sent to a central laboratory for processing, thus negating the need for a patient to visit an outpatient clinic or local surgery (Bateman, 2020). The laboratory assay must be validated and provide sufficient accuracy to support accurate clinical decision-making. This onset of a remote, patient centric approach to sampling brings with it the chance to fundamentally challenge and change the healthcare delivery model. Sampling and appointments can be decentralized, and most routine supportive care can be virtual. This does not mean the end of the hospital or GP visit, but it does mean that the approach used can be fitted to the requirements of the individuals involved and the healthcare decisions that need to be made. Remote sampling and consultations are more time efficient (Ballester et al., 2018; Prasad et al., 2020; Russo et al., 2016) and this means that not only can they be scheduled around peoples' daily lives better but also any face-to-face appointments can be prioritized for people where in-person consultation is truly needed. For overstretched front-line staff and health systems, this is likely to be a very attractive proposition.
Research has also shown that dried blood spot sampling versus conventional blood sampling conferred cost savings across the ecosystem in renal transplant and hemato-oncology patients (Martial et al., 2016). In this study, switching to home sampling was associated with a societal cost reduction of 43% for hemato-oncology patients and 61% for nephrology patients per blood draw. From a healthcare perspective, costs reduced by 7% for hemato-oncology patients and by 21% for nephrology patients due to the replacement of office-based tests with home-based sampling.
So the evidence suggests that virtual care provides a mostly positive patient experience and is more efficient for the health service. Could this also help reduce the number of people not "turning up" for medical appointment (if the consultation comes to them)? Research has shown that the high levels of "no shows" to hospital appointments have a large impact on the organizational structure and cost to a health provider (Dantas et al., 2018; Jefferson et al., 2019; Mohammadi et al., 2018). Although no research has been carried out on this to date, it is possible that the efficient use of home sampling could reduce this "appointment missing," and this more optimized supportive care for patients could offer additional benefits on the downstream impacts to service. Another potential benefit of home sampling could be the time freed up for those more in need of face-to-face contact and better decisions on how to balance the two approaches. There are benefits and limitations to both home-based and in clinic approaches-for example, home care approaches which are decentralized have been shown to give better individualized, immediate care, but along with this, the responsibility for monitoring is largely delegated to technical devices, patients, and their families (Oudshoorn, 2009). Face-to-face appointments in the clinic have been shown to be preferred over telemedicine in specific circumstances such as when patients have low self-management ability and/or depending on the purpose of the consultation (e.g. initial discussions about terminal disease, which may have additional, unspoken support needs; Chudner et al., 2019; Derkson et al., 2020). Designing an integrated approach based on the person's needs may be most beneficial for all. For example, in 2019, Jiang and colleagues found that correctly timing a face-to-face consultation increased a patient's ability to accurately find information digitally and administer self-care post consultation. Integrated approaches also bring the potential to save more face-to-face consultation time for personalized conversations and supportive care, leaving more simple tests and interventions to be carried out at home.
The authors suggest the use of home blood sampling may have positive impacts on a person's overall well-being by allowing intrusive interventions to be carried out within a familiar home environment. A survey was taken of 39 adult kidney transplant patients who underwent both traditional venepuncture and microsampling approaches for monitoring of their condition and the current blood sampling burden was quantified using two measures: anxiety and travel requirements (Scuderi et al., 2020). A third of participants (n = 13) reported blood test anxiety and 44% (n = 17) spent more than an hour just to travel to the required phlebotomy site for standard of care. Preference between the two approaches was also explored: 85% (n = 33) preferred microsampling approaches and 95% (n = 37) expressed an interest in collecting their microsample themselves at home. This demonstrates a clear patient preference and willingness to give microsampling a go for monitoring post-transplantation recovery progress.
1.2 Exploring the Barriers to Home Sampling
Given the efficiencies and benefits of home-based care, why is not remote patient centric microsampling more rapidly adopted everywhere? The answers may rest with people and the hurdles involved in fundamentally changing established care pathways and healthcare cultures in which people are already working at maximum capacity to deliver what they know, let alone try something new.
The scientific and technological aspects of patient centric microsampling have accelerated in the past 5 years and are driving the field of healthcare in the home; this chapter aims to focus on many of the key concerns that have been heard through working in the clinic, with patients, and developing technologies. The aim is that by starting a discussion around each of these concerns and by proposing potential solutions, developers and leaders of the future will be able to co-create the approaches with the relevant end users and speed up the realization of benefits that these sampling processes can bring.
1.2.1 Barrier One-The Discord Between Innovation and Practice
Recent events of the pandemic in 2020 have shown us that all healthcare systems run at a finite capacity. To implement change, the very same people who rely on established approaches have to, instead, adopt and implement something brand new, while maintaining their high standard of care in challenging times.
The expertise behind the development of highly sensitive microsampling technology has, up until now, been mostly confined to pharmaceutical companies and private laboratories and was...
