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Review
The impact of new trends in POCTs for companion diagnostics, non-invasive testing and molecular diagnostics Expert Rev. Mol. Diagn. 15(6), 815–827 (2015)
David Huckle Adams Business Associates, 2 Buckingham Place, Bellfield Road, High Wycombe HP13 5HW, UK [email protected]
Point-of-care diagnostics have been slowly developing over several decades and have taken on a new importance in current healthcare delivery for both diagnostics and development of new drugs. Molecular diagnostics have become a key driver of technology change and opened up new areas in companion diagnostics for use alongside pharmaceuticals and in new clinical approaches such as non-invasive testing. Future areas involving smartphone and other information technology advances, together with new developments in molecular biology, microfluidics and surface chemistry are adding to advances in the market. The focus for point-of-care tests with molecular diagnostic technologies is focused on advancing effective applications. KEYWORDS: companion diagnostics . microfluidics . molecular diagnostics . next-generation sequencing . non-invasive testing
.
personalized medicine
.
POCT . reimbursement
.
Past reviews of the point-of-care testing (POCT) market [1,2] have focused on the issues of acceptance that sometimes complex assays could be carried out by non-technical personnel and the inevitable resistance to changes required in healthcare delivery. With some justification, the early objections were supported by major questions on product quality [3]. Early POCT attempts from the 1980s onward were indeed relatively crude and could only be justified as approximate yes–no (qualitative) analyses [4]. Gradually, as both technology and supportive developments related to liquid handling, signal detection and format advanced, these objections were addressed and overcome. By the middle of the current decade, it had become truly an implementation issue with the non-technical, regulatory and reimbursement issues the dominant hurdles to be overcome for POCT acceptance [2]. The important message is now not to confuse POCT, which is a market segment, with technologies that are used and being developed in central laboratory segments. Various terms have been used:
informahealthcare.com
10.1586/14737159.2015.1033405
telehealth . telemonitoring .
POCT – An analytical procedure performed outside of a central laboratory usually by a trained but not professional person or by self-testing. . Companion diagnostics (CDx) – Tests that are used to analyze genetic variation of patient response to particular therapeutic treatments. This can be drug selection, treatment effectiveness and/or toxicity to the therapy. . Stratified medicine is using diagnostic tests to determine drug selection with the potential for prognostic information on the outcome. The selection of the therapeutic approach and the correct drug dosage for individual patients becomes personalized medicine (PDx): pharmacogenomics. The use of tests such as glucose and international normalized ratio (INR) by self-testing POCTs for patient management is separate from use of the same parameters for diagnosis by professionals that can be made by either laboratory tests or POCT in a clinic situation [3,5,6].
2015 Informa UK Ltd
ISSN 1473-7159
815
Expert Review of Molecular Diagnostics Downloaded from informahealthcare.com by Nyu Medical Center on 06/06/15 For personal use only.
Review
Huckle
In considering trends in the POCT sector, it is important to recognize the driving force that has developed globally from the pressures on healthcare delivery, both in demand and from the costs [7]. The in vitro diagnostics (IVD) market has continued to grow in test numbers but more slowly as cost reduction pressures have been forced upon the sector. As a result, companies have moved their attention to the two faster growing areas of the market: the favored technology is molecular diagnostics (MDx) and the favored segment is POCT [8]. The main aim of clinicians now is to have POCTs that provide diagnostic information for acute conditions (infections, cardiac, embolisms and deep vein thrombosis), where treatment can be implemented at an early stage, and some chronic conditions (diabetes, anemia and anti-coagulant therapy) [5]. POCT analysis has been dominated for the last decade by the U.S. market and for glucose testing on a more global basis [9,10]. The situation is now changing partly due to demographic changes, with emerging markets without a strong central laboratory infrastructure using POCT as the first line for introduction of diagnostics: this has practical benefits of avoiding installation costs as well as more immediate patient care [10]. The most recent demonstration of this has been the Ebola outbreak in West Africa. The need for diagnostics, in an area with limited laboratory testing, is for an urgent result at low cost, but with sufficient funding from aid and other agencies to justify development of test products as a viable commercial venture [11,12]. The major trends in the POCT market are now concerned with applying both established technologies and the newer developments directly into POCT usage [13]. The way that these technologies are used and their application areas are the objectives of this review. The areas are: . . . . . .
New IVD technology areas, for example, agglutination testing (INR). CDx and PDx, for example, drug selection. MDx, for example, infectious diseases and cancer. Non-invasive testing, for example, pre-natal testing. Ethical and economic issues, for example, POCT in genetic testing and impact on health insurance. Future developments, for example, Smartphone impact and home testing capability.
A consequence of these developments has been increased research and development for POCT implementation within companies in order to have platforms that can meet demands of the target customers and the specific test analyte. However, another important trend with the increase in POCT testing has been the controls imposed on reimbursement by procuring agencies. The most visible example has been reduced reimbursement for glucose test strips in the US, Europe and Japan [14,6,15]. Bedside testing is now an established option for use of POCT for routine health status parameters, such as blood gases, and so on. This trend is being extended with increased use in emergency departments with Cardiac Triage [16] and toxicology [17], although user needs are not yet being fully met [18]. 816
New technology areas for POCT diagnostics
While the use of POCT for glucose continues to increase, driven mainly by adoption of testing in emerging countries such as China and India where diabetes is now recognized as being of high incidence [19], there are other areas where POCT testing is replacing conventional laboratory testing [18]. The trend is here similar to that for glucose testing for diabetics, when testing outside of the laboratory, even by the patient, can be used to adjust or change treatment. The driver being the patient need rather more than the technology being developed [16]. The closest analogy to that of glucose testing is for patients on anti-coagulant therapy. The dosage of drug, particularly warfarin, required for effective treatment is patient dependent and a standard dosage can only be a starting point. Determination of the clotting rate, in a test method called INR, is a good measurement of effectiveness. Self-testing by the patient allows self-adjustment of the drug dose in conjunction with clinical advice. The approach avoids use of time and facilities by both patient and clinician. In examining new technologies and their applications, there are important differences between the total POCT market and professional use of POCTs, where laboratory testing is an available option. This is helped by separating the tests that are more commonly used from those that are available but have more limited application: FIGURE 1. A major argument against POCT in the past has been the reduced precision and accuracy of these tests compared with laboratory tests [1]. Advances in technology for POCTs have largely removed these concerns and the performance issues are less about the capability of POCTs and more about results in the hands of the non-expert user. There have been significant changes in the last few years with increased acceptance of cardiac markers and a steadily growing market for INR for those on anticoagulant therapy in the developed nations. The utility of POCTs for HIV/AIDS and TB [20] has been recognized as effective tools in Africa and some Asian countries, such as India, where these are endemic conditions. Use of POCTs in Field Station facilities is believed to bring faster diagnosis and earlier treatment, but the realities of implementation are huge [21]. There is a trend for technologies through other developments, technical and/or political, to enhance a move toward POCT and to open up new areas previously of no interest or unobtainable. For example, MDx were seen as being for laboratory testing due to their complexity and need to avoid contamination in amplification methods, but there is an increasing trend for these to be targeted specifically for POCT use. Demonstration of the trend was the FDA approval in January 2015 of the first MDx test for influenza A/B for use in non-laboratory applications (but not home use) under the clinical laboratory improvement act waive mechanism [22,23]. In addition, there are drivers outside of the major advanced markets because of the limited infrastructure in the emerging nations. The widespread populations in some of these countries, notably China, India and Africa, means that most tests are POCT format favored [24]. Expert Rev. Mol. Diagn. 15(6), (2015)
New trends in POCTs
fully accepted that POCT devices require suitable means of storing results for later Glucose downloading and/or transfer to patient Blood gas analysis and electrolytes record systems [13,16]. The proliferation of Urine dipsticks POCT devices, particularly the shift Pregnancy and Infertility–largely OTC Selftoward either home or self-testing, has test Cardiac markers increased the importance of connectivity Occult blood with some mitigation from wireless transClotting time, for high dose heparin users fer of test information. As the test techHaemoglobin nology has increased, notably with MDx, Rapid strep testing an increased need for interpretation of INR for anticoagulant therapy users the result has become more important in addition to the transfer of data through connectivity systems. Responsibility for the transfer of information is not well Figure 1. Common and less used POCT tests, 2015. defined, but will rest largely with the proPOCT: Point-of-care testing. fessional staff involved [13]. Adapted with permission from Adams Business Associates, personalized medicine and The easiest way to achieve all the point-of-care tests, ABA 310, April 2014. demands above is to develop fully integrated systems. The problem faced for For many years, biosensors and specific lab-on-chip options POCT use is that unlike laboratories, where samples are were proposed as viable alternatives to conventional laboratory brought together in sufficient numbers to be run on dedicated tests and shown to be possible for most analytes. The main instruments, in primary care there are small numbers of problems for acceptance were related to manufacture and end patients requiring tests from across the whole range of possible product costs, with success only achieved in a limited number diagnostic tests. The impracticality of this is clear and would of uses. The trends that have provided support to both these have to be met by replication of the cost-effective central labotechnologies have been automation, microfluidics and nano- ratory that on a small scale would be uneconomic. The consetechnology [25], surface technology [26], improved computing quence has been the development of a number of individual for testing and control of POCT instruments and the drive for dedicated but integrated systems specifically for POCT [18]. use of Smartphones for information storage and transmis- These platforms have not attempted to cover every possible test sion [27]. The impact of Smartphones for POCT is already but to address those important clinical areas where there is being seen with wearable devices increasing rapidly that can be both a need for quick information and where treatment can be used to monitor physical parameters such as blood pressure made. and record results, such as blood glucose levels. Although the INR test is a good example of a POCT, with The important items that are driving development of new potential to follow commercial development similar to glucose platforms and approaches are: testing, there has been limited adoption outside of a few major markets because of the reimbursement structures that would . Test result quality – Accuracy and sensitivity being the most reduce revenues for the professionals, particularly in consulimportant. tancy visits [14]. Of greater concern for the trend in this type of . No sample handling – A challenge if precise sample volume application is that such clearcut and established clinical benefits needed. are few. Even though selection and dosage of drugs is receiving . No sample processing – Need for whole blood or other ready attention through CDx, as discussed next, the long-term experimatrix (urine, saliva). ence with new drugs will not be there to allow testing and . Total assay time – Clinicians not prepared to wait longer dose adjustment by the patient for some years to come. than ca. 20 min for the result. . Portability of system – For use around the facility and to Companion diagnostics & personalized medicine avoid setting up a laboratory. Both CDx and PDx are methods close to the patient and . Result recording and transmission – Easy reading at the time should fit into POCT [29]. In practice, the finding that multiple of test, storage of result and capability to transfer data to markers or combination of genes determine the most effective healthcare facility record database: Connectivity. targets has meant the complexity and interpretation of many Widely used POCTs
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Review
Available but less used POCTs Drug and toxicity tests D-dimer for thromboembolism Haemostasis assessment (coagulation) Magnesium Lactate Lipids Microalbumin and creatinine Haemoglobin A1c (HbA1c) HIV Influenza Helicobacter pylori (for ulcers) Transcutaneous bilirubin Tuberculosis HIV/AIDS–widely in Africa and India
The above items are clinically biased but apply possibly even more in non-clinical sectors, such as biodefence, environmental, food/beverage and veterinary [28] areas, where the use of POCTs is increasing as they are effectively field methods where data retention is even more important. In the past, it has been informahealthcare.com
tests required, such as genetic tests using MDx, testing has been largely carried out in central laboratories [30]. How this might change and the impact on the POCT market is unclear but is part of a major change to the established pharmaceutical business paradigm and the necessity of moving from the 817
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Huckle
Grifols (Spain, for US$1.675 B) but retained diagnostics that supported its core pharma business [36,37]. Study Sector Market figures Ref. The size for these markets is even (year) more complex than that for POCT itself, PWC Personalized medicine 2010 – US$232 B US$452 B by 2015 [38] with general overlap between the CDx, personalized diagnostics and stratified Vision gain Stratified medicine 2012 – US$1.5 billion [39] (2013) 15% pa growth medicine markets. A further complication is that many market analyses combine Trimark Companion 2010 – US$1.3 B 2013 – US$2.2 B [40] diagnostics with pharmaceuticals in a (2014) diagnostics products 20% pa growth total overall market. It is important thereReportlinker Drug discovery US$32 billion pa with [41] fore to be clear on the definitions of US$1 B in cancer which products are included. The trends drug discovery and in the market have been assessed by trials in 2012 many analysts, but the separation of Adapted with permission from Adams Business Associates. POCT from laboratory testing is less precise: see TABLE 1 [38–41]. one-size-fits-all drug treatment approach to drug selection based The most reasonable approach is to accept that for POCT, on genetically established or other marker response. Although whether this is CDx, PDx or MDx applications in stratified the current focus has been on using high-cost MDx tests, these medicine, it is a fast-growing market with a multi-million dolcan be used to determine effective markers that can be assayed lar recurring market [8,38–41]. There is potential for the diagnosby alternative, lower cost tests, such as immunoassays [31,32]. tics concerned in the stratified medicine market for POCT use It is of relevance to note the research applications that have to reach for some figure well above 1 billion dollars per year created new business areas for diagnostic companies and intro- (>> US$1–2 billion pa) in the next 5 years [8,38–41]. However, duced new players into the market through application of commercial efforts for POCT in this part of the market need MDx testing to areas that ultimately define drug selection to address many issues not only the technical capabilities covering [33]: required but also the business support both in funding and in expertise to establish a mutually beneficial deal with any . Drug discovery – The whole process of linking disease condipharma partner [42]. tions with effective drugs. . Drug toxicity – Early identification of drugs with a toxic Research funding for personalized & stratified medicine impact even when effective in treating the condition. CDx tend to be funded directly between a pharmaceutical . Biomarker identification – Use of genetic analysis to identify company developing a drug and a diagnostic company with effective pathways that can be monitored by other technolo- expertise or a widely applicable platform technology. The pergies, for example, ELISA assays, still leading to PDx. sonalized or stratified medicine approach is sponsored more by
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Table 1. Published market figures for personalized and stratified medicine.
These test areas for individual patients are not matched to the high-throughput testing structure of routine clinical laboratories so that there is POCT testing for each of the above [34]. The new technologies and applications have been enhanced or enabled by feature technologies: in this case such as microfluidics and automated miniaturization together with advances in informatics and connectivity to meet the demands outlined above for POCT products in general [25,35]. The microfluidics approach has been supported by the advances in nanotechnology that have allowed not only the reduction in size but also improved sensitivity and precision of the POCT assay [25]. There has been a trend for companies to acquire diagnostic businesses to bring the new expertise in house. This has generally not worked well, due to different business cultures and the favored business model has been to use partnerships focused on the drug-diagnostic link. An example of internal acquisition is that of Novartis. It acquired Vivacta in December 2012 (for US$90 M) with a view to enhancing its capability for CDx products and in mid-2013 sold its transfusion diagnostics business to 818
government agencies as a means to resolve increasingly high healthcare costs. The expected savings will be through more effective treatments and targeting drugs to patients where there is a proven likelihood of a response and toxicity problems are minimized [29,43]. In Europe, through the EU programs as in TABLE 2 [44], and globally there are a number of projects not necessarily labeled as ‘stratified medicine’ but all are meeting through their research programs the similar objectives suggested above. Within these projects, POCT might be used in order to monitor patient responses, general wellbeing or point to genetic approaches. Each of these EU-funded projects involves a number of small medium enterprises internationally and use of POCT and MDx methods as analytical methods to determine genetic links of disease conditions and drug response. In addition, various countries have action plans for PDx involving some element of POCT that are funded nationally and are designed to meet specific needs identified in those countries. Life is not always simple in these national programs Expert Rev. Mol. Diagn. 15(6), (2015)
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New trends in POCTs
due to influence of local politics. For example, in Germany, the role of genetic testing is carefully regulated and has an impact on the application of stratified medicine with the research that leads up to it. In 2013, it was stated: [45]: “Personal Genomic Testing has been highlighted as under German Genetic Diagnostics Law (2010) this is only permitted when ordered by a licensed physician who must provide the results together with counseling. This does not affect on-line services outside of Germany. The new service from biologis (Frankfurt) appears to be in breach of the law although offering additional background info and limiting its services to carrier status or where preventative or therapeutic actions are possible.” Development trends of POCT for personalized medicine & companion diagnostics
Review
Table 2. European Union programs for stratified medicine and companion diagnostics, 2014. Program
Objectives
Funding
COMBACTE (an IMI Project)
“New drugs for bad bugs”
US$260.4 M
TRANSLOCATION (an IMI project)
Cell well permeability study for new therapies
US$39.2 M
Global Alliance of Leading Drug Discovery and Development Centers
400 groups for new targets and therapies
165 projects
EMIF Initiative
Patient data framework in Alzheimer’s and obesity
US$76 M
STEMBANCC project
Use of human-induced pluripotent stem cells to test drugs for safety and efficacy
US$74 M
COMPACT
New ways to deliver biologic drugs into the body
US$40 M
ORBITO
Laboratory tests and computer modeling for more accurate drug behavior predictions
US$33 M
K4DD
Drug-binding kinetics
US$28 M
US$51 M for four International Rare Diseases Use of epigenetic, genetic, and The key development appears to be research programs Consortium (IRDiRC) whole-genome sequencing data to enhanced technology for MDx that can be over 6 years address rare diseases used in POCT format since these areas Adapted with permission from Adams Business Associates, personalized medicine and point-of-care tests, ABA logically fit with direct patient interaction 310, April 2014. and into the areas where immediate action can be taken [46]. While treatment of cancer will remain a hospi- approval might rest on having the diagnostic test, but it is the tal- or clinic-based procedure, it is the other areas requiring drug that will be reimbursed. This leaves the test cost to be immediate drug therapy without surgical interaction that offer covered by the hospital, the drug company or perhaps eventuthe most likely direction for POCT in these uses [13]. There ally following a scheme similar to glucose testing in which remains the issue of where testing in these sectors should be car- instruments are placed free by the drug company and consumried out. There are groups in Switzerland suggesting that PDx ables paid for directly to the diagnostic company [48–50]. In the US, the Association of Medical Diagnostics Manufacshould be linked to POCT while others in the UK have a strong turers set up a working party to address the problems with the belief that this type of testing should be carried out on a national FDA [51] . The questions are, if the total reimbursement is for basis with defined central laboratory testing. Support can be seen the drug, how is the diagnostic reimbursed? or . . . if they are for laboratory use due to the complexity of the technology using DNA amplification and/or microarrays and whether whole- separately covered how can issues of silo budgeting be resolved? genome or single-nucleotide polymorphism analysis is used The problem could be solved, or might even be a driver, with reflecting the early stage of implementation of these technologies. the disease-related group concept where there is a total figure It is suggested, therefore, that the various technologies for to cover all procedures, diagnostics and treatments with a single personalized and stratified medicine will likely move into the reimbursement figure [49]. One practical trend from PDx will be using the diagnostic hospital clinic as a first stage of implementation, in much the same way as POCT itself, with the more contentious and diffi- information in order to define the effective drug dosage for individual patients [52,53]. This can be seen as an extension of existing cult CDx procedures following later [47]. Regulatory controls in this area have an extra dimension POCT for such as INR in order to define the correct therapeutic with a mix of legal barriers regarding patenting of DNA, genes dose for anti-coagulant therapy. From a slightly different perspecor the like that will limit a company to innovate effective prod- tive POCT PDx already exists with use of blood glucose moniucts and various ‘Rights Groups’ that are against any form of toring to alert patients that levels are falling and insulin genetic testing in order to make selection decisions. Although administration or sugar is needed depending on the type of diathe general regulatory approval for a CDx, whether for labora- betes but based on outcomes rather than pharmacogenomics. An indication of the trend for future development for pertory or POCT use, is no different to that for IVDs in general, the problem for this type of product is reimbursement. The sonalized and stratified medicine comes in part from a multireimbursement environment for CDx is not attractive. Drug national study by Edinburgh University (ESRC Genomics informahealthcare.com
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Review
Huckle
Forum, UK) [54]. The main drivers were the perception that there would be improved clinical outcomes and that it would be cost-effective. Out of the seven (7) countries approached for feedback, six (6) had some level of stratified medicine, with South Africa being the exception. The other six countries were China, Finland, Israel, Luxembourg, Mexico and UK. European countries saw few barriers to research but other countries cited research funding and access to international research networks as barriers. The comments above were underlined by all countries seeing barriers to technology translation and implementation with a lack of funding for translational research, healthcare reimbursement regimes and a general lack of understanding among policy makers. This useful crosssection of countries highlighted the local issues for POCT with only China, Israel and Mexico seeing application to infectious diseases as a priority area but one needing international support. Point-of-care testing & molecular diagnostics
The basic principle for MDx assays is similar to that for other IVD tests relying on ligand receptor binding, with the difference being that in MDx the target analyte is a nucleic acid. Development of MDx for POCT applications is in rapid but early development stage, but the core technology is established and shown to be viable in several applications and in different segments, including low-cost cases. Overall costs will be a main POCT adoption factor for MDx tests [32,43,55]. An important question, possibly without a definite answer, is concern over the target hierarchy with respect to genotype and phenotype for diagnostic procedures, but MDx allows direct and earlier stage identification of either of these key health parameters. At the gene level MDx tests are able to indicate weaknesses in genetic makeup that have a high correlation with defined conditions and allows assessment of susceptibility to inherited diseases or those where an appropriate if unknown trigger can initiate a disease state [56]. The complexity of the early DNA-probe-based tests limited their use to central laboratory segments but, by reference to the preceding analysis of personalized healthcare, strong arguments for MDx by POCT methods can be put forward [47]. Protein diagnostics can be used as effective surrogate DNA markers for the disease state or monitoring its treatment, and this continues to be an effective route for routine analysis. The research trend is to focus directly on those DNA and RNA markers that are produced and control the various biological mechanisms through genetic modification at the gene structure stage. Research has shown that small variations in DNA in the coding region of genes, called single-nucleotide polymorphisms, alter protein structures, change alleles or give rise to Lewis blood type differences [57]. More recent research has shown that environmental or other factors give rise to changes in the DNA of individuals mainly by methylation, epigenetics, with profound health and human trait impacts but without the changes being inherited [58]. Technology developments provided two options for the analysis of these very small amounts of target DNA or RNA that 820
are now the core technologies used in MDx [59,60]. The amount of target DNA can be amplified either by hybridization techniques that recycle the product at each stage or by signal amplification. A ‘middle of the road’ series of technologies utilize linear or circular extension of the target DNA, which is repeated over a period of time to provide sufficient material to be analyzed with acceptable precision. In the most widely used amplification technology, called PCR, the target DNA and an appropriate primer are mixed with a thermally stable polymerase, usually Taq polymerase. The mixture is carefully taken through controlled cycles of heating and cooling in a thermal cycler where the increase in DNA available for analysis becomes exponential. The DNA produced can then be determined by a range of analytical techniques, which for diagnostic purposes rely on use of fluorescent labeling of the reaction mixture. Alternative approaches have been use of isothermal temperature PCR and signal amplification, particularly chemiluminescence [61,62], that are making POCT methods more accessible. The first few POCT products have now been approved [22], and much research is targeted at new applications for POCTMDx products, mostly directed at infectious diseases, relying on automated and/or fully integrated systems. The demand from developing countries with local disease problems has intensified [63–65]. The 2014/15 Ebola outbreak in West Africa has demonstrated the commercial drive for products designed for these low-cost markets when there is major need and funding is being made available for both development and purchase of the end product [12]. This use highlights the emphasis on greater patient benefit versus access to a hospital system with its central laboratory, particularly in resource-limited environments [66]. As might be expected from the stage of POCT MDx technology, development users are finding ways of exploiting the technology for their individual needs, irrespective of the original uses of the commercial innovators that remain relatively few in number. The technical effort is now around adding features to the technology to make it more widely usable in relevant POCT segments. Examples with the groups concerned are given in TABLE 3. A small number of companies have taken the MDx technology in a different direction with detailed analysis of the gene structure with complete and/or part genome sequencing as a means of definitive DNA measurement [67]. Sequencing technology has itself developed with the current generation of next-generation sequencing, being considered as well as the established amplification technologies [68,69]. A major hurdle of the sequencing approach has been its high cost but as technology has developed, with strong links to automation and computing advances, costs have fallen dramatically and the time to obtain the result much reduced to hours instead of days or weeks. This time frame makes sequencing still a central laboratory activity, but if this is reduced to a few hours, as proposed in the single molecule systems, scope for use in POCT will grow [70]. Expert Rev. Mol. Diagn. 15(6), (2015)
New trends in POCTs
Review
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Table 3. Point-of-care molecular diagnostic development examples, 2015. Platform
Application
Organization
POCT MDx
Malaria testing
Alberta Health Services (Canada)
POCT MDx
Infectious diseases
Mayo Clinic (Rochester, MN, USA)
POCT MDx
Sexually transmitted diseases
Johns Hopkins University (Baltimore, MD, USA)
POCT MDx
Self-testing for HIV
McGill University (Canada)
POCT MDx cartridge amplification system
Infectious diseases with
Review
The impact of new trends in POCTs for companion diagnostics, non-invasive testing and molecular diagnostics Expert Rev. Mol. Diagn. 15(6), 815–827 (2015)
David Huckle Adams Business Associates, 2 Buckingham Place, Bellfield Road, High Wycombe HP13 5HW, UK [email protected]
Point-of-care diagnostics have been slowly developing over several decades and have taken on a new importance in current healthcare delivery for both diagnostics and development of new drugs. Molecular diagnostics have become a key driver of technology change and opened up new areas in companion diagnostics for use alongside pharmaceuticals and in new clinical approaches such as non-invasive testing. Future areas involving smartphone and other information technology advances, together with new developments in molecular biology, microfluidics and surface chemistry are adding to advances in the market. The focus for point-of-care tests with molecular diagnostic technologies is focused on advancing effective applications. KEYWORDS: companion diagnostics . microfluidics . molecular diagnostics . next-generation sequencing . non-invasive testing
.
personalized medicine
.
POCT . reimbursement
.
Past reviews of the point-of-care testing (POCT) market [1,2] have focused on the issues of acceptance that sometimes complex assays could be carried out by non-technical personnel and the inevitable resistance to changes required in healthcare delivery. With some justification, the early objections were supported by major questions on product quality [3]. Early POCT attempts from the 1980s onward were indeed relatively crude and could only be justified as approximate yes–no (qualitative) analyses [4]. Gradually, as both technology and supportive developments related to liquid handling, signal detection and format advanced, these objections were addressed and overcome. By the middle of the current decade, it had become truly an implementation issue with the non-technical, regulatory and reimbursement issues the dominant hurdles to be overcome for POCT acceptance [2]. The important message is now not to confuse POCT, which is a market segment, with technologies that are used and being developed in central laboratory segments. Various terms have been used:
informahealthcare.com
10.1586/14737159.2015.1033405
telehealth . telemonitoring .
POCT – An analytical procedure performed outside of a central laboratory usually by a trained but not professional person or by self-testing. . Companion diagnostics (CDx) – Tests that are used to analyze genetic variation of patient response to particular therapeutic treatments. This can be drug selection, treatment effectiveness and/or toxicity to the therapy. . Stratified medicine is using diagnostic tests to determine drug selection with the potential for prognostic information on the outcome. The selection of the therapeutic approach and the correct drug dosage for individual patients becomes personalized medicine (PDx): pharmacogenomics. The use of tests such as glucose and international normalized ratio (INR) by self-testing POCTs for patient management is separate from use of the same parameters for diagnosis by professionals that can be made by either laboratory tests or POCT in a clinic situation [3,5,6].
2015 Informa UK Ltd
ISSN 1473-7159
815
Expert Review of Molecular Diagnostics Downloaded from informahealthcare.com by Nyu Medical Center on 06/06/15 For personal use only.
Review
Huckle
In considering trends in the POCT sector, it is important to recognize the driving force that has developed globally from the pressures on healthcare delivery, both in demand and from the costs [7]. The in vitro diagnostics (IVD) market has continued to grow in test numbers but more slowly as cost reduction pressures have been forced upon the sector. As a result, companies have moved their attention to the two faster growing areas of the market: the favored technology is molecular diagnostics (MDx) and the favored segment is POCT [8]. The main aim of clinicians now is to have POCTs that provide diagnostic information for acute conditions (infections, cardiac, embolisms and deep vein thrombosis), where treatment can be implemented at an early stage, and some chronic conditions (diabetes, anemia and anti-coagulant therapy) [5]. POCT analysis has been dominated for the last decade by the U.S. market and for glucose testing on a more global basis [9,10]. The situation is now changing partly due to demographic changes, with emerging markets without a strong central laboratory infrastructure using POCT as the first line for introduction of diagnostics: this has practical benefits of avoiding installation costs as well as more immediate patient care [10]. The most recent demonstration of this has been the Ebola outbreak in West Africa. The need for diagnostics, in an area with limited laboratory testing, is for an urgent result at low cost, but with sufficient funding from aid and other agencies to justify development of test products as a viable commercial venture [11,12]. The major trends in the POCT market are now concerned with applying both established technologies and the newer developments directly into POCT usage [13]. The way that these technologies are used and their application areas are the objectives of this review. The areas are: . . . . . .
New IVD technology areas, for example, agglutination testing (INR). CDx and PDx, for example, drug selection. MDx, for example, infectious diseases and cancer. Non-invasive testing, for example, pre-natal testing. Ethical and economic issues, for example, POCT in genetic testing and impact on health insurance. Future developments, for example, Smartphone impact and home testing capability.
A consequence of these developments has been increased research and development for POCT implementation within companies in order to have platforms that can meet demands of the target customers and the specific test analyte. However, another important trend with the increase in POCT testing has been the controls imposed on reimbursement by procuring agencies. The most visible example has been reduced reimbursement for glucose test strips in the US, Europe and Japan [14,6,15]. Bedside testing is now an established option for use of POCT for routine health status parameters, such as blood gases, and so on. This trend is being extended with increased use in emergency departments with Cardiac Triage [16] and toxicology [17], although user needs are not yet being fully met [18]. 816
New technology areas for POCT diagnostics
While the use of POCT for glucose continues to increase, driven mainly by adoption of testing in emerging countries such as China and India where diabetes is now recognized as being of high incidence [19], there are other areas where POCT testing is replacing conventional laboratory testing [18]. The trend is here similar to that for glucose testing for diabetics, when testing outside of the laboratory, even by the patient, can be used to adjust or change treatment. The driver being the patient need rather more than the technology being developed [16]. The closest analogy to that of glucose testing is for patients on anti-coagulant therapy. The dosage of drug, particularly warfarin, required for effective treatment is patient dependent and a standard dosage can only be a starting point. Determination of the clotting rate, in a test method called INR, is a good measurement of effectiveness. Self-testing by the patient allows self-adjustment of the drug dose in conjunction with clinical advice. The approach avoids use of time and facilities by both patient and clinician. In examining new technologies and their applications, there are important differences between the total POCT market and professional use of POCTs, where laboratory testing is an available option. This is helped by separating the tests that are more commonly used from those that are available but have more limited application: FIGURE 1. A major argument against POCT in the past has been the reduced precision and accuracy of these tests compared with laboratory tests [1]. Advances in technology for POCTs have largely removed these concerns and the performance issues are less about the capability of POCTs and more about results in the hands of the non-expert user. There have been significant changes in the last few years with increased acceptance of cardiac markers and a steadily growing market for INR for those on anticoagulant therapy in the developed nations. The utility of POCTs for HIV/AIDS and TB [20] has been recognized as effective tools in Africa and some Asian countries, such as India, where these are endemic conditions. Use of POCTs in Field Station facilities is believed to bring faster diagnosis and earlier treatment, but the realities of implementation are huge [21]. There is a trend for technologies through other developments, technical and/or political, to enhance a move toward POCT and to open up new areas previously of no interest or unobtainable. For example, MDx were seen as being for laboratory testing due to their complexity and need to avoid contamination in amplification methods, but there is an increasing trend for these to be targeted specifically for POCT use. Demonstration of the trend was the FDA approval in January 2015 of the first MDx test for influenza A/B for use in non-laboratory applications (but not home use) under the clinical laboratory improvement act waive mechanism [22,23]. In addition, there are drivers outside of the major advanced markets because of the limited infrastructure in the emerging nations. The widespread populations in some of these countries, notably China, India and Africa, means that most tests are POCT format favored [24]. Expert Rev. Mol. Diagn. 15(6), (2015)
New trends in POCTs
fully accepted that POCT devices require suitable means of storing results for later Glucose downloading and/or transfer to patient Blood gas analysis and electrolytes record systems [13,16]. The proliferation of Urine dipsticks POCT devices, particularly the shift Pregnancy and Infertility–largely OTC Selftoward either home or self-testing, has test Cardiac markers increased the importance of connectivity Occult blood with some mitigation from wireless transClotting time, for high dose heparin users fer of test information. As the test techHaemoglobin nology has increased, notably with MDx, Rapid strep testing an increased need for interpretation of INR for anticoagulant therapy users the result has become more important in addition to the transfer of data through connectivity systems. Responsibility for the transfer of information is not well Figure 1. Common and less used POCT tests, 2015. defined, but will rest largely with the proPOCT: Point-of-care testing. fessional staff involved [13]. Adapted with permission from Adams Business Associates, personalized medicine and The easiest way to achieve all the point-of-care tests, ABA 310, April 2014. demands above is to develop fully integrated systems. The problem faced for For many years, biosensors and specific lab-on-chip options POCT use is that unlike laboratories, where samples are were proposed as viable alternatives to conventional laboratory brought together in sufficient numbers to be run on dedicated tests and shown to be possible for most analytes. The main instruments, in primary care there are small numbers of problems for acceptance were related to manufacture and end patients requiring tests from across the whole range of possible product costs, with success only achieved in a limited number diagnostic tests. The impracticality of this is clear and would of uses. The trends that have provided support to both these have to be met by replication of the cost-effective central labotechnologies have been automation, microfluidics and nano- ratory that on a small scale would be uneconomic. The consetechnology [25], surface technology [26], improved computing quence has been the development of a number of individual for testing and control of POCT instruments and the drive for dedicated but integrated systems specifically for POCT [18]. use of Smartphones for information storage and transmis- These platforms have not attempted to cover every possible test sion [27]. The impact of Smartphones for POCT is already but to address those important clinical areas where there is being seen with wearable devices increasing rapidly that can be both a need for quick information and where treatment can be used to monitor physical parameters such as blood pressure made. and record results, such as blood glucose levels. Although the INR test is a good example of a POCT, with The important items that are driving development of new potential to follow commercial development similar to glucose platforms and approaches are: testing, there has been limited adoption outside of a few major markets because of the reimbursement structures that would . Test result quality – Accuracy and sensitivity being the most reduce revenues for the professionals, particularly in consulimportant. tancy visits [14]. Of greater concern for the trend in this type of . No sample handling – A challenge if precise sample volume application is that such clearcut and established clinical benefits needed. are few. Even though selection and dosage of drugs is receiving . No sample processing – Need for whole blood or other ready attention through CDx, as discussed next, the long-term experimatrix (urine, saliva). ence with new drugs will not be there to allow testing and . Total assay time – Clinicians not prepared to wait longer dose adjustment by the patient for some years to come. than ca. 20 min for the result. . Portability of system – For use around the facility and to Companion diagnostics & personalized medicine avoid setting up a laboratory. Both CDx and PDx are methods close to the patient and . Result recording and transmission – Easy reading at the time should fit into POCT [29]. In practice, the finding that multiple of test, storage of result and capability to transfer data to markers or combination of genes determine the most effective healthcare facility record database: Connectivity. targets has meant the complexity and interpretation of many Widely used POCTs
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Available but less used POCTs Drug and toxicity tests D-dimer for thromboembolism Haemostasis assessment (coagulation) Magnesium Lactate Lipids Microalbumin and creatinine Haemoglobin A1c (HbA1c) HIV Influenza Helicobacter pylori (for ulcers) Transcutaneous bilirubin Tuberculosis HIV/AIDS–widely in Africa and India
The above items are clinically biased but apply possibly even more in non-clinical sectors, such as biodefence, environmental, food/beverage and veterinary [28] areas, where the use of POCTs is increasing as they are effectively field methods where data retention is even more important. In the past, it has been informahealthcare.com
tests required, such as genetic tests using MDx, testing has been largely carried out in central laboratories [30]. How this might change and the impact on the POCT market is unclear but is part of a major change to the established pharmaceutical business paradigm and the necessity of moving from the 817
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Grifols (Spain, for US$1.675 B) but retained diagnostics that supported its core pharma business [36,37]. Study Sector Market figures Ref. The size for these markets is even (year) more complex than that for POCT itself, PWC Personalized medicine 2010 – US$232 B US$452 B by 2015 [38] with general overlap between the CDx, personalized diagnostics and stratified Vision gain Stratified medicine 2012 – US$1.5 billion [39] (2013) 15% pa growth medicine markets. A further complication is that many market analyses combine Trimark Companion 2010 – US$1.3 B 2013 – US$2.2 B [40] diagnostics with pharmaceuticals in a (2014) diagnostics products 20% pa growth total overall market. It is important thereReportlinker Drug discovery US$32 billion pa with [41] fore to be clear on the definitions of US$1 B in cancer which products are included. The trends drug discovery and in the market have been assessed by trials in 2012 many analysts, but the separation of Adapted with permission from Adams Business Associates. POCT from laboratory testing is less precise: see TABLE 1 [38–41]. one-size-fits-all drug treatment approach to drug selection based The most reasonable approach is to accept that for POCT, on genetically established or other marker response. Although whether this is CDx, PDx or MDx applications in stratified the current focus has been on using high-cost MDx tests, these medicine, it is a fast-growing market with a multi-million dolcan be used to determine effective markers that can be assayed lar recurring market [8,38–41]. There is potential for the diagnosby alternative, lower cost tests, such as immunoassays [31,32]. tics concerned in the stratified medicine market for POCT use It is of relevance to note the research applications that have to reach for some figure well above 1 billion dollars per year created new business areas for diagnostic companies and intro- (>> US$1–2 billion pa) in the next 5 years [8,38–41]. However, duced new players into the market through application of commercial efforts for POCT in this part of the market need MDx testing to areas that ultimately define drug selection to address many issues not only the technical capabilities covering [33]: required but also the business support both in funding and in expertise to establish a mutually beneficial deal with any . Drug discovery – The whole process of linking disease condipharma partner [42]. tions with effective drugs. . Drug toxicity – Early identification of drugs with a toxic Research funding for personalized & stratified medicine impact even when effective in treating the condition. CDx tend to be funded directly between a pharmaceutical . Biomarker identification – Use of genetic analysis to identify company developing a drug and a diagnostic company with effective pathways that can be monitored by other technolo- expertise or a widely applicable platform technology. The pergies, for example, ELISA assays, still leading to PDx. sonalized or stratified medicine approach is sponsored more by
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Table 1. Published market figures for personalized and stratified medicine.
These test areas for individual patients are not matched to the high-throughput testing structure of routine clinical laboratories so that there is POCT testing for each of the above [34]. The new technologies and applications have been enhanced or enabled by feature technologies: in this case such as microfluidics and automated miniaturization together with advances in informatics and connectivity to meet the demands outlined above for POCT products in general [25,35]. The microfluidics approach has been supported by the advances in nanotechnology that have allowed not only the reduction in size but also improved sensitivity and precision of the POCT assay [25]. There has been a trend for companies to acquire diagnostic businesses to bring the new expertise in house. This has generally not worked well, due to different business cultures and the favored business model has been to use partnerships focused on the drug-diagnostic link. An example of internal acquisition is that of Novartis. It acquired Vivacta in December 2012 (for US$90 M) with a view to enhancing its capability for CDx products and in mid-2013 sold its transfusion diagnostics business to 818
government agencies as a means to resolve increasingly high healthcare costs. The expected savings will be through more effective treatments and targeting drugs to patients where there is a proven likelihood of a response and toxicity problems are minimized [29,43]. In Europe, through the EU programs as in TABLE 2 [44], and globally there are a number of projects not necessarily labeled as ‘stratified medicine’ but all are meeting through their research programs the similar objectives suggested above. Within these projects, POCT might be used in order to monitor patient responses, general wellbeing or point to genetic approaches. Each of these EU-funded projects involves a number of small medium enterprises internationally and use of POCT and MDx methods as analytical methods to determine genetic links of disease conditions and drug response. In addition, various countries have action plans for PDx involving some element of POCT that are funded nationally and are designed to meet specific needs identified in those countries. Life is not always simple in these national programs Expert Rev. Mol. Diagn. 15(6), (2015)
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New trends in POCTs
due to influence of local politics. For example, in Germany, the role of genetic testing is carefully regulated and has an impact on the application of stratified medicine with the research that leads up to it. In 2013, it was stated: [45]: “Personal Genomic Testing has been highlighted as under German Genetic Diagnostics Law (2010) this is only permitted when ordered by a licensed physician who must provide the results together with counseling. This does not affect on-line services outside of Germany. The new service from biologis (Frankfurt) appears to be in breach of the law although offering additional background info and limiting its services to carrier status or where preventative or therapeutic actions are possible.” Development trends of POCT for personalized medicine & companion diagnostics
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Table 2. European Union programs for stratified medicine and companion diagnostics, 2014. Program
Objectives
Funding
COMBACTE (an IMI Project)
“New drugs for bad bugs”
US$260.4 M
TRANSLOCATION (an IMI project)
Cell well permeability study for new therapies
US$39.2 M
Global Alliance of Leading Drug Discovery and Development Centers
400 groups for new targets and therapies
165 projects
EMIF Initiative
Patient data framework in Alzheimer’s and obesity
US$76 M
STEMBANCC project
Use of human-induced pluripotent stem cells to test drugs for safety and efficacy
US$74 M
COMPACT
New ways to deliver biologic drugs into the body
US$40 M
ORBITO
Laboratory tests and computer modeling for more accurate drug behavior predictions
US$33 M
K4DD
Drug-binding kinetics
US$28 M
US$51 M for four International Rare Diseases Use of epigenetic, genetic, and The key development appears to be research programs Consortium (IRDiRC) whole-genome sequencing data to enhanced technology for MDx that can be over 6 years address rare diseases used in POCT format since these areas Adapted with permission from Adams Business Associates, personalized medicine and point-of-care tests, ABA logically fit with direct patient interaction 310, April 2014. and into the areas where immediate action can be taken [46]. While treatment of cancer will remain a hospi- approval might rest on having the diagnostic test, but it is the tal- or clinic-based procedure, it is the other areas requiring drug that will be reimbursed. This leaves the test cost to be immediate drug therapy without surgical interaction that offer covered by the hospital, the drug company or perhaps eventuthe most likely direction for POCT in these uses [13]. There ally following a scheme similar to glucose testing in which remains the issue of where testing in these sectors should be car- instruments are placed free by the drug company and consumried out. There are groups in Switzerland suggesting that PDx ables paid for directly to the diagnostic company [48–50]. In the US, the Association of Medical Diagnostics Manufacshould be linked to POCT while others in the UK have a strong turers set up a working party to address the problems with the belief that this type of testing should be carried out on a national FDA [51] . The questions are, if the total reimbursement is for basis with defined central laboratory testing. Support can be seen the drug, how is the diagnostic reimbursed? or . . . if they are for laboratory use due to the complexity of the technology using DNA amplification and/or microarrays and whether whole- separately covered how can issues of silo budgeting be resolved? genome or single-nucleotide polymorphism analysis is used The problem could be solved, or might even be a driver, with reflecting the early stage of implementation of these technologies. the disease-related group concept where there is a total figure It is suggested, therefore, that the various technologies for to cover all procedures, diagnostics and treatments with a single personalized and stratified medicine will likely move into the reimbursement figure [49]. One practical trend from PDx will be using the diagnostic hospital clinic as a first stage of implementation, in much the same way as POCT itself, with the more contentious and diffi- information in order to define the effective drug dosage for individual patients [52,53]. This can be seen as an extension of existing cult CDx procedures following later [47]. Regulatory controls in this area have an extra dimension POCT for such as INR in order to define the correct therapeutic with a mix of legal barriers regarding patenting of DNA, genes dose for anti-coagulant therapy. From a slightly different perspecor the like that will limit a company to innovate effective prod- tive POCT PDx already exists with use of blood glucose moniucts and various ‘Rights Groups’ that are against any form of toring to alert patients that levels are falling and insulin genetic testing in order to make selection decisions. Although administration or sugar is needed depending on the type of diathe general regulatory approval for a CDx, whether for labora- betes but based on outcomes rather than pharmacogenomics. An indication of the trend for future development for pertory or POCT use, is no different to that for IVDs in general, the problem for this type of product is reimbursement. The sonalized and stratified medicine comes in part from a multireimbursement environment for CDx is not attractive. Drug national study by Edinburgh University (ESRC Genomics informahealthcare.com
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Forum, UK) [54]. The main drivers were the perception that there would be improved clinical outcomes and that it would be cost-effective. Out of the seven (7) countries approached for feedback, six (6) had some level of stratified medicine, with South Africa being the exception. The other six countries were China, Finland, Israel, Luxembourg, Mexico and UK. European countries saw few barriers to research but other countries cited research funding and access to international research networks as barriers. The comments above were underlined by all countries seeing barriers to technology translation and implementation with a lack of funding for translational research, healthcare reimbursement regimes and a general lack of understanding among policy makers. This useful crosssection of countries highlighted the local issues for POCT with only China, Israel and Mexico seeing application to infectious diseases as a priority area but one needing international support. Point-of-care testing & molecular diagnostics
The basic principle for MDx assays is similar to that for other IVD tests relying on ligand receptor binding, with the difference being that in MDx the target analyte is a nucleic acid. Development of MDx for POCT applications is in rapid but early development stage, but the core technology is established and shown to be viable in several applications and in different segments, including low-cost cases. Overall costs will be a main POCT adoption factor for MDx tests [32,43,55]. An important question, possibly without a definite answer, is concern over the target hierarchy with respect to genotype and phenotype for diagnostic procedures, but MDx allows direct and earlier stage identification of either of these key health parameters. At the gene level MDx tests are able to indicate weaknesses in genetic makeup that have a high correlation with defined conditions and allows assessment of susceptibility to inherited diseases or those where an appropriate if unknown trigger can initiate a disease state [56]. The complexity of the early DNA-probe-based tests limited their use to central laboratory segments but, by reference to the preceding analysis of personalized healthcare, strong arguments for MDx by POCT methods can be put forward [47]. Protein diagnostics can be used as effective surrogate DNA markers for the disease state or monitoring its treatment, and this continues to be an effective route for routine analysis. The research trend is to focus directly on those DNA and RNA markers that are produced and control the various biological mechanisms through genetic modification at the gene structure stage. Research has shown that small variations in DNA in the coding region of genes, called single-nucleotide polymorphisms, alter protein structures, change alleles or give rise to Lewis blood type differences [57]. More recent research has shown that environmental or other factors give rise to changes in the DNA of individuals mainly by methylation, epigenetics, with profound health and human trait impacts but without the changes being inherited [58]. Technology developments provided two options for the analysis of these very small amounts of target DNA or RNA that 820
are now the core technologies used in MDx [59,60]. The amount of target DNA can be amplified either by hybridization techniques that recycle the product at each stage or by signal amplification. A ‘middle of the road’ series of technologies utilize linear or circular extension of the target DNA, which is repeated over a period of time to provide sufficient material to be analyzed with acceptable precision. In the most widely used amplification technology, called PCR, the target DNA and an appropriate primer are mixed with a thermally stable polymerase, usually Taq polymerase. The mixture is carefully taken through controlled cycles of heating and cooling in a thermal cycler where the increase in DNA available for analysis becomes exponential. The DNA produced can then be determined by a range of analytical techniques, which for diagnostic purposes rely on use of fluorescent labeling of the reaction mixture. Alternative approaches have been use of isothermal temperature PCR and signal amplification, particularly chemiluminescence [61,62], that are making POCT methods more accessible. The first few POCT products have now been approved [22], and much research is targeted at new applications for POCTMDx products, mostly directed at infectious diseases, relying on automated and/or fully integrated systems. The demand from developing countries with local disease problems has intensified [63–65]. The 2014/15 Ebola outbreak in West Africa has demonstrated the commercial drive for products designed for these low-cost markets when there is major need and funding is being made available for both development and purchase of the end product [12]. This use highlights the emphasis on greater patient benefit versus access to a hospital system with its central laboratory, particularly in resource-limited environments [66]. As might be expected from the stage of POCT MDx technology, development users are finding ways of exploiting the technology for their individual needs, irrespective of the original uses of the commercial innovators that remain relatively few in number. The technical effort is now around adding features to the technology to make it more widely usable in relevant POCT segments. Examples with the groups concerned are given in TABLE 3. A small number of companies have taken the MDx technology in a different direction with detailed analysis of the gene structure with complete and/or part genome sequencing as a means of definitive DNA measurement [67]. Sequencing technology has itself developed with the current generation of next-generation sequencing, being considered as well as the established amplification technologies [68,69]. A major hurdle of the sequencing approach has been its high cost but as technology has developed, with strong links to automation and computing advances, costs have fallen dramatically and the time to obtain the result much reduced to hours instead of days or weeks. This time frame makes sequencing still a central laboratory activity, but if this is reduced to a few hours, as proposed in the single molecule systems, scope for use in POCT will grow [70]. Expert Rev. Mol. Diagn. 15(6), (2015)
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Table 3. Point-of-care molecular diagnostic development examples, 2015. Platform
Application
Organization
POCT MDx
Malaria testing
Alberta Health Services (Canada)
POCT MDx
Infectious diseases
Mayo Clinic (Rochester, MN, USA)
POCT MDx
Sexually transmitted diseases
Johns Hopkins University (Baltimore, MD, USA)
POCT MDx
Self-testing for HIV
McGill University (Canada)
POCT MDx cartridge amplification system
Infectious diseases with
