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LAMP is a factor 5 to 10 less sensitive than qPCR. This is problematic for LAMP because qPCR will always be picked over LAMP in a lab environment. This means that if your kit is to be used in a lab, then it has to compete with qPCR and be at least as good. If your kit is meant for a setting outside of the lab (point-of-care), it is acceptable to lose some sensitivity. The point-of-care nature makes up for the loss in sensitivity. | LAMP is a factor 5 to 10 less sensitive than qPCR. This is problematic for LAMP because qPCR will always be picked over LAMP in a lab environment. This means that if your kit is to be used in a lab, then it has to compete with qPCR and be at least as good. If your kit is meant for a setting outside of the lab (point-of-care), it is acceptable to lose some sensitivity. The point-of-care nature makes up for the loss in sensitivity. | ||
Revision as of 08:43, 21 October 2020
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Rapidemic
Human Practices
As part of our human practices, our team aimed to view our project from a variety of outlooks: from the societal or individual needs to the economical viability, but also what is legally required and certain ethical considerations. On this page, we will report the insights that interactions with players from the medical world, the academic and the business world have provided us during the entirety of our project (figure 1). We have compiled here how our initial project idea was shaped by the experience and knowledge from the stakeholders.
Figure 1. Our team collected insights from a variety of players in the field
Question: Which challenge is iGEM Leiden 2020 going to take on?
Input
Our team started the iGEM experience with a very open attitude, hoping to address an important societal issue. Our team decided to work in the field of infectious diseases. As we dug into literature and talked to experts, we aimed to identify a need in this vast field.
World Health Organization
As part of their effort in emergency preparedness and response, the WHO keeps a record of the outbreaks that occur yearly. The latest outbreaks include Yellow fever, Influenza A virus, Ebola virus, Plague, MERS-CoV, Measles, Dengue, as well as SARS-CoV-2. Certain diseases, such as Ebola, are recurrent in tropical and Subsaharan regions 1. Yellow Fever 2 is endemic in Africa and Central and South America, whereas the endemic regions affected by Dengue 3 are even larger. These outbreaks of diseases need to be addressed with funds but also medical developments. This is all the more important in regions with fewer resources.
McNerney, R. (2015). Diagnostics for developing countries. Diagnostics, 5(2), 200-209 4.
Lower-income countries have a higher incidence and prevalence of communicable diseases, because of a lack of correct diagnosis and follow-up treatment for the patients, due to geographical or financial reasons. As a consequence, they often face difficulties preventing the further transmission of these diseases.
Dr Assica Permata, M.D. currently working on TB in a research environment
Dr Permata told us about the situation in Indonesia, where patients in large cities usually could get tested. However, in smaller cities, where the laboratory facilities are not optimal, the samples have to be sent to larger facilities and patients may have to wait days to weeks for the results.
Peeling & Mabey, 2010 5.
In the developing world, there is a need for point of care tests, as they can help speed up the diagnosis of bacterial, parasitic, and viral diseases. Additionally, the quality of the tests has to be improved. Systems for quality control and improving training in the use of the kit can help improve the quality of the tests.
Robin van Houdt, microbiologist at the Dutch Association for Medical Microbiology and the UMC Amsterdam
Robin van Houdt told us that RDTs are also very useful in developed, high-income countries where hospitals dispose of sophisticated laboratories. RDTs could be used to tests patients upon entry in the hospital, for instance, identifying the patients that should be treated in isolation. This could help save a lot of time and money, and is better for the patient’s wellbeing. RDTs could also be used to quickly test an entire ward if an infection does occur. This could then prevent spread to other parts of the hospital.
Huram Konjen, Chief executive officer of Dianox
Mr. Konjen told us that the need to improve diagnostics lies in the need to address and reduce the elevated costs associated with testing. These costs are mainly lab costs such as equipment and the staff.
Integration
Infectious diseases are the most important enemy of the health of humankind, translated as seasonal colds, urinary infections, but also haemorrhagic fevers, respiratory affections or septic shocks.
When our team first sat down around a table to discuss the purpose of our project, a very obvious, threatening situation was cooking on the other side of the planet. The Covid-19 pandemic seeped through each of our conversations and interfered with our habits and way of life. It reminded us of the damage and chaos that a few nano/micrometers of biology can cause in entire populations.
Particularly in the middle and low resource areas, the increased emergence of these outbreaks and the lack of sufficient medical resources yield an important death toll, even for preventable and treatable diseases 6.
Our team therefore decided to take on the challenge of developing an economical and accessible rapid diagnostic test (RDT) for infectious diseases.
Rapid diagnostic tests can be used with minimal equipment and are suitable for emergency situations, where low resources are available, but not only. The speed of the tests is also particularly appreciated as delays in diagnosis can result in the poorer prognosis of the patients. For some neglected or less prevalent infectious diseases, there is a true, urgent need for more specific, accurate, and accessible diagnostic tools. Diagnosis of other, more prevalent diseases such as Malaria, require more qualitative tests, in a market flooded with low-cost tests.
Question: Developing a rapid diagnostic test for infectious diseases: where do we start?
Input
The first step to develop a rapid diagnostic test is to determine the technical, scientific means at our disposal and to compare it to existing methods, to identify a starting point. To do so, our team turned to our predecessors in the iGEM community, in the hope to learn from their experience and launch our ambitious quest.
Niek Savelkoul, iGEM 2017 Wageningen Mantis & Founder of Scope Biosciences
Niek shared his experience in the iGEM 2017 Mantis project, in which they attempted to develop a multiplex rapid test for infectious diseases. However, they did not manage to get a functional kit. He said that using a cell receptor sensor presented too many limitations, such as a delay due to the transcription and the fact that it contained living material. He suggested that a cell-free system would be preferred.
Prof. dr. Janneke van de Wijgert, professor in epidemiology UMC Utrecht & Liverpool
According to professor Janneke van de Wijgert, in general, a molecular-based diagnostic kit has an advantage over antigen/antibody-based or chemical biomarker-based kits when considering reliability. However, reliability depends on the type and complexity of the disease.
Dr Peter Bredenbeek, assistant professor in Virology LUMC
With Dr. Bredenbeek we discussed which scientific considerations were important. He stated that to be successful, our kit should be at least as sensitive as PCR, which is able to detect up to 4-5 copies/mL of sampled blood. He also encouraged us to include a positive and negative control in each of the kits.
Thomas Caltagirone, CEO of Alpagen LLP
We discussed with Dr. Caltagirone his publication of 2018, on a technique that is able to cause a color change in the reaction with the help of a DNAzyme, called the GQ-EXPAR system 7. He told us that the amplification of the target in the tube would help to reduce false positives and increase the intensity of the colorimetric output.
Dr Armand Paauw, Scientist at TNO Defence, Security and Safety, & Dr Hans van Leeuwen, Senior Scientist at TNO
LAMP is a factor 5 to 10 less sensitive than qPCR. This is problematic for LAMP because qPCR will always be picked over LAMP in a lab environment. This means that if your kit is to be used in a lab, then it has to compete with qPCR and be at least as good. If your kit is meant for a setting outside of the lab (point-of-care), it is acceptable to lose some sensitivity. The point-of-care nature makes up for the loss in sensitivity.
iGEM EPFL 2019 ViTest
Thereafter, we reached out to the iGEM 2019 team from EPFL, that worked on developing a sensor for wine diseases as they used the RPA technique for amplification. They told us that RPA is highly specific and sensitive, but that as a result contaminations can interfere with the results. They suggested using the TwistDX kit for RPA.
Integration
At the start of our project, we reached out to the 2017 iGEM Mantis project, to understand the challenges they faced and to identify our starting point. One of their challenges, integrating living cells with an antibody library in a test kit, was not feasible. Our team, therefore, decided to opt for a cell-free system, comprised of enzymes and rather stable nucleic acids. This also enabled to bypass the challenge that antigen tests may face and allows to directly identify the pathogen using molecular techniques.
Literature also suggested that the RPA method is more sensitive than PCR (the golden standard, and reference technique for many infectious diseases) in a controlled environment 8. Additionally, RPA is a good option as it does not require a power source and would enable equipment-free use.
Finally, technical considerations pushed forwards by many parties was the need for a qualitative, easily-detectable and foolproof output, which would leave no room for interpretation. Our team therefore got inspired by the common ELISA tests. By using a peroxidase DNAzyme with hemin, positive samples would undergo an immediate and very clear color change. Our team has also thought about the integration of the controls in the kit as seen on our Hardware page
Question: How can we identify a niche in the vast and complex field of infectious diseases?
Input
The preliminary steps in our project indicated that there is a need for more and better diagnostics. Nevertheless, the need may differ depending on the disease and the sociogeographical situation of the patient. In the quest for an application, our team reached out to patients and experts in the field to understand where the specific medical, but also societal needs and challenges lie, for each of the diseases.
Dr Peter Bredenbeek, assistant professor in Virology LUMC
The first pathogen we naturally thought of was the pathogen responsible for the current pandemic, the coronavirus, as no molecular test had yet been approved. However, Dr. Bredenbeek strongly discouraged us from choosing SARS-CoV-2 as an application. We would be competing with very large companies that possess extensive resources and large networks. These companies are racing for financial gain and scientific novelty in a highly pressured environment. Aligned with iGEM's advice and expectations, we decided not to linger on this topic and instead, look into other applications.
René Paulussen, managing director Mondial Diagnostics
Our team set out to further research other pathogens, of which Vibrio cholerae. However, Mr. Paulussen discouraged us from developing a test kit for this disease. When an outbreak occurs in a community, only the first patients are diagnosed. Other patients with the same symptoms are treated for cholera without further testing. This is due to the epidemic nature of cholera. The cholera market is, therefore, an extremely low margin market for high development costs, which would not be viable for a project like Rapidemic.
Dr Hein Sprong, Research coordinator & scientist at Centre for Infectious Disease Control (CIb), RIVM, Netherlands
Dr. Sprong is a researcher in the zoonosis of infectious diseases, with a strong interest in tick-borne diseases. Dr. Sprong was very enthusiastic about the idea of a self-test for Lyme disease. He even qualified it as a "Nobel Prize idea" if we manage to detect the B. burgdorferi (the bacteria responsible for Lyme disease) nucleic acid in the area around the tick bite. However, he warned us that the concentration can be very low and that for diagnosis, a high rate of false positives/negatives can occur. Additionally, out of the many, many people bitten by ticks, only a minute fraction develops Lyme disease. Therefore, performing tests would be meaningless as the test results would not very informative.
Dr Lieselotte Hardy, Doctor at Institute of Tropical Medicine Antwerp, Belgium
Dr. Hardy focuses on infectious diseases and their diagnosis and has worked on projects in Sub Saharan Africa and Asia. She mentioned that the diagnosis of bacterial bloodstream infections is still insufficient and that a rapid diagnostic test (RDT) for these infections would be fruitful. However, she also mentioned that in the case of bacterial sepsis, the concentration of the bacterial agent can be very low. This input was confirmed by one of Hardy's colleagues, who is a medical doctor. While there is a need for better diagnosis of this affection, even in hospital settings, diagnosis of sepsis would require multiplex testing of various pathogens, which might not be accommodated by our kit.
Dr Heleen Koudijs, Tropical doctor
Dr. Koudijs also discussed TB as a potential disease our technology could be applied to. However, she mentioned that Genexpert has good control over the market. A drawback Genexpert has is that the kit is quite expensive.
Mosquito-born diseases
Dr Heleen Koudijs, Tropical doctor
Dr. Koudijs proposed several mosquito-borne diseases, one of these is Malaria. According to Dr. Koudijs, the market for RDT for malaria is quite saturated. There are a lot of cheap RDT's available for malaria. The reason why they are so cheap is because the companies are funded by organizations such as the WHO, Gates Foundation, and other NGO's. As a consequence, malaria might not be the best disease to focus on.
Dengue and Malaria patients
We questioned patients diagnosed with Dengue (3) and Malaria (3) in Honduras, Argentina, Zambia, Congo, Costa Rica, and Indonesia about their diagnostic procedures. Some of the patients stated that they experienced difficulties in reaching a doctor to get tested, demonstrating that access to healthcare is not always easy. The patients experienced a very slow and inaccurate diagnosic procedure of the dengue virus and stated that it needs to be improved. Malaria patients also had to undergo repeated testing, even when tested in centers with experienced doctors. The patients expressed that they would prefer a quicker diagnostic procedure that would require less blood sampling.
Hélène van Oorschot, Student in medicine
With Mrs. van Oorschot we discussed malaria and dengue as potential applications. She discouraged mosquito-borne diseases in general because if there is an epidemic, quarantine would not help. Apart from this, with malaria as an application, our kit would also compete with the medicine itself. This is because malaria medicine is cheap and readily available. For example, if the patient has the symptoms of malaria, but microscopy does not diagnose malaria, the patient is still given malaria medicine. In addition, testing for dengue is questionable as there is no cure available. Patients can therefore only be treated for their symptoms, rather than the source of disease, such as preventing dehydration.
Disease X and Epidemic preparedness
Professor Pim Martens, Maastricht Sustainability Institute, director of the International Centre for Integrated assessment and Sustainable development (ICIS), School of Business and Economics, founder of AnimalWise and member of House of Animals, member of Dutch Health Council
Professor Martens worked on predicting the spread of Malaria and the associated risks. He told us that Malaria is still a very important disease to focus on in diagnostics as it is multifactorial and complex. Deforestation, increasing travel behavior, climate change, intensive farming and the increase in population density are increasing the emergence and the spread of novel pathogens, likely from zoonotic origin. Therefore, when we asked him which pathogen he would like to detect he responded:
"I would go for the one we don't know yet"
Dr Armand Paauw, Scientist at TNO Defence, Security and Safety, & Dr Hans van Leeuwen, Senior Scientist at TNO
The two scientists at TNO told us that Influenza would be a good application, since this is a rapidly mutating virus and has potential to cause an epidemic/pandemic. Besides this, the high mutation rate is something that can be addressed well by the modular nature of the kit. However, one should then be able to prove that the test can be quickly used for various diseases and, by extension, adapted to novel diseases.
Willem Mees van der Bijl, Director IDE Netherlands at IDE Group
Mr. Van der Bijl mentored us on the kit development. Rather than trying to implement one product that can detect any pathogen, he advised focusing the development effort on a specific diagnostic application at first and extending the application later to the diagnosis of other diseases.
Integration
A DNA/RNA sensor could be adapted to any human infectious disease. Soon after reaching out to the experts in the field of infectious diseases, our team realized that identifying a niche in the field of diagnostics of infectious diseases would require us to balance the science of our kit with many external factors. These, for instance, include the medical need for an RDT, the patient's preferences, the identification of a gap in the diagnostic market, but also the feasibility of the implementation, due to regulation and logistics.
Our team was driven by a desire to address a societal and humanitarian need for better diagnosis. The input of the patients was triggering, as it made us very invested in improving the diagnostic procedures. Pinpointing an application pushed us to acknowledge and work with the qualities and the limitations of the science of our kit, to inherently match its application. While we allowed ourselves to aspire to ambitious goals, we made it a prime point in this project to identify a niche and an application that would be realistic and viable.
At first, by focussing on specific diseases such as Lyme disease, Cholera, bloodstream or urinary infections, and TB, our team aimed to respond to a specific diagnostic need. However, we then soon realized that when doing so, we were positioning ourselves in direct competition with the sensitivity, cost, quality, and accuracy of the current methods of diagnosis of these diseases, without being certain that our kit would be able to truly answer an unmet need.
While conducting more integrated and holistic research, our team looked into current diagnostic methods for mosquito-borne diseases such as Dengue, Yellow Fever, and Malaria. Patients and doctors confirmed that there are struggles with the detection of these diseases, particularly prevalent in tropical zones. Today, these diseases affect hundreds of millions of people each year. It is predicted that these diseases will likely spread towards the North as the effects of climate change will force the vectors of these diseases upwards, affecting even more people. However, these diseases do not progress through direct human-to-human transmission. A rapid diagnostic test could replace the "golden standard" diagnosis of these diseases in certain low-income areas. However, as many rapid tests for Malaria have already been developed, it may be unconstructive to compete with diagnostic tools already on the market. As a consequence, we were not completely conviced that this application would be the optimal niche for our rapid and modular application.
We then took a step back an reflected on the scientific content of the tests we had imagined. The use of primers in a molecular test would entail that they can be replaced for any pathogen, emphasizing the kit's potential for modularity. Therefore, we presented a novel idea to the experts, which was received with great enthusiasm: tackling novel outbreaks with epidemic potential at their source to prevent their spread. However, they warned that it is difficult to convince stakeholders in the field of a modular idea, as it might raise skepticism on the feasability of such an ambitious endeavour. Therefore, our team looked into diseases that have great pandemic potential, which rapidly led us to respiratory RNA viruses, such as the group of Orthomyxoviridae and Coronaviridae. These pathogens are known to cause disease and mutate quickly, making them very likely to cause a next great outbreak. Our kit could be used to rapidly address the need for tests, even in the most remote and low resource areas.
Timeline
Exploring the needs in rapid diagnostics → Mosquito-borne diseases → Disease X → Respiratory-borne RNA viruses
Questions: Who is going to use our kit? Where is our kit going to be used?
Input
From an accessibility viewpoint, self RDTs are optimal as they do not require medical assistance and can be distributed and sold in pharmacies, directly to the population. We interviewed patients from different areas of the world, business players and doctors that have worked in areas with limited lab or hospital access to understand whether self-testing is the most appropriate option.
Dr Sophie van Baalen, Researcher team medical technology for Rathenau institute
Even though we aimed our kit to be used by patients, we did not only discuss patients as possible end-user with Dr van Baalen. According to her, the benefit of having the patient perform the test themselves is that there is no need for professionals to perform them. However, the benefit of having professionals handling the kit is that you have better quality control and immediate follow-up care. Moreover, it enables the collection of epidemiologic data from the tests. In the setting of outbreaks of infectious diseases, this crucial information would enable real-time monitoring of the spread.
Patients: Malaria, TB, Dengue and SARS-CoV-2
We first questioned patients (13) from around the world diagnosed with Malaria, Dengue and Tuberculosis to compare the diagnostic need and settings as well as to understand their preferences.
When asked whether they would feel comfortable performing a finger prick test or a nasal swab themselves, the vast majority responded that they would not feel comfortable doing so, and prefer to be assisted. We also asked whether they would trust a test performed by a doctor more or less than a self-RDT. Out of the nine people that answered this question, six said that they would trust a self-RDT less than a test conducted by a doctor.
We then also asked COVID-19 patients about their diagnostic experience. We found that if a patient does not experience symptoms that are unique or characteristic of a disease, or if the probability of getting the disease is not (very) high, patients do not think of purchasing a test for this specific disease unless they had been advised by their doctor.
Additionally, we questioned the risk of self-RDTs for the patients' health. Indeed, if a patient performs a self-RDT and tests positive, the patient would not be in a setting where it can immediately be provided with treatment if necessary. If the patient tests negative, the patient cannot test further for other diseases, nor have access to additional medical care, such as IV fluids or analgesia.
Finally, a patient reminded us that in certain countries, social security is a well-structured system that enables reimbursement to the patients. If a patient in these regions self-tests, but then also wishes to visit a doctor for a second opinion, self RDTs might be an additional procedure, thus an additional cost. A solution would be to sell RDTs solely under prescription.
René Paulussen, managing director Mondial Diagnostics
As it is challenging to bring a testkit to the market, Mr Paulussen discouraged us from making a home self-test right away. Indeed, companies first have to build up and a reputation and credibility. He, therefore, suggested starting by developing the kit for laboratories with limited infrastructure, where the tests can be conducted by minimally trained staff. This way, the quality can be safeguarded and, in turn, improves the credibility and reputation. Later on, the kit can be made more accessible to less/non trained individuals.
Dr Heleen Koudijs, Tropical doctor
While working in Ethiopia, Dr Koudijs found that a large share of the population is analphabetic. Therefore, she does not trust the patient to perform the test themselves. She thus recommended developing the kit with health centers or health professionals working in posts in rural villages as end-users. They are probably the best way to reach rural villages as they are greatly respected by the locals.
Eric de Coster, Medical coördinator in the General Infectious Disease Control and Travel Advice
Mr de Coster told us about what happens when a patient tests positive for a disease in health centers (GGD) in the Netherlands. The GGD tests the patients, but also gathers the data (results) and sends the anonymized files to the National Institute for Public Health and Environment (RIVM). Collecting data is crucial as it can help to manage the spread of diseases and subsequently determine decisionmaking on a governmental level.
How can we then ensure that our kit is userfriendly?
Identifying the end-users of the tests is crucial as it is inherently related to the design of the kit and eventually the reliability of the outcome. Therefore, we sought to know which considerations are important in order to build a physical kit and to render it userfriendly and the result unequivocal.
Dr Heleen Koudijs, Tropical doctor
Dr. Koudijs has worked with RDT's during her time in Ethiopia. However, according to her, the corona test kit used by doctors in Ethiopia lacks a clear description and has a very confusing design. This resulted in unnecessary errors and false results. Therefore, Dr. Koudijs highly recommended ensuring that a clear instruction manual (pamphlet) is present as well as a simple, clear kit design.
John Tonkinson, Chief Business Development Officer DCN DX
Mr. Tonkinson told us to make use of engineering to complete the biological limitations that the kit might present. He strongly emphasized anticipating the slightest errors that one could make. The results should also not leave any room for interpretation, as this is a source of errors. Clear color-coding to show the outcome is a good example to prevent interpretation.
René Paulussen, managing director Mondial Diagnostics
Mr Paulussen also had some remarks about the design of our kit. He proposed to use the KISS strategy (Keep It Simple, Stupid). Therefore, the explanations of the kit should be given in pictograms, such that they can be understood by everyone, regardless of their education level. The different reagents (such as the buffer and the sample) that should be added together should be color-coded as well.
Professor dr Aldrik Velders, Nanobiotechnology at Wageningen University & Dr Vittorio Saggiomo, Organic Chemistryl
The two chemists working on developing microfluidic devices told us that it is important to keep the handling of the device to a minimum and to limit the possibility of contaminations to ensure a reliable outcome. Thus, ideally, the kit should be as passive as possible and happen in a single reaction tube.
Integration
Certain limitations of self-testing, such as the increased chance of false results due to human error and the absence of appropriate data gathering, indicate that patients should probably not be entrusted with the manipulation of the kits themselves.
The input gathered indicates that patients as well as doctors and developers think it is best to consider trained staff as users of the kits. Patients are not eager to perform medical procedures themselves, even minor ones. The patients overall would not prefer performing a kit from the comfort of their homes as they would like to get proper follow-up care in the case of a severe disease.
Out of concern for equality, we do not want to compromise the accessibility nor the quality, and instead find the right balance between both. Therefore, our team thinks that the tests could be used by hospital staff, but also NGOs or trained technicians that could be mobilized in the field or in crowded areas such as airports and in cities. The kits could also be performed by staff in schools, essential businesses, or elderly homes. Performing tests by trained staff also facilitates data collection for epidemiology, so important in outbreaks of infectious diseases. Trained staff will also be more inclined to properly dispose of the kit, which contains material from a potentially infected patient (see Disposal).
Furthermore, the experts reminded us of certain considerations that, when applied, can help safeguard the quality of the test. The test should be made as intuitive, easy and robust as possible. Indeed, our team attempted to minimize the amount of handling by conducting the reactions with buffers that could accommodate the different components and conduct reactions with the least amount of material possible (fewer reaction tubes, centrifugation steps, using generic buffers or adapt the pH).
To avoid interpretation, experts confirmed that a colorimetric output is a good option. The test would be given along with a color indicator, as well as an integrated positive and negative control in the test, with the aim to minimize human error.
More about the design of the kit can be found on the Hardware page.
Timeline
Exploring the needs in rapid diagnostics → Mosquito-borne diseases → Disease X → Respiratory-borne RNA viruses
Question: How can we ensure that the cost of a test does not compromise the accessibility to all?
Input
Proper healthcare is a basic need, however, it has to be paid for to be sustained. We attempted to understand the cost of exitsting RDTs, and how we can make ours affordable for all.
Niek Savelkoul, iGEM 2017 Wageningen Mantis & Founder of Scope Biosciences
Niek told us that behind projects to improve diagnostics lie a strong philanthropic desire. As many RDTs are developed for low resource areas, the tests cannot be too expensive as they would not be used in the regions in need.
Prof. dr. Janneke van de Wijgert, professor in epidemiology UMC Utrecht & Liverpool
Professor van de Wijgert said that most RDTs are not widely available. In resource-poor countries, almost all tests are considered too expensive.
John Tonkinson, Chief Business Development Officer DCN DX
Mr. Tonkinson told us that typically during pandemics, tests are funded or subsidized by foundations working with local governments (such as the Gates foundation). He told us that they set the cost depending on the budget and that the test kits should then be produced for that price. Therefore, the tests have to be economical and the prices have to be set at the beginning of the development process. He also told us that producing in very large amounts, as is done for Malaria RDTs, enables us to drastically reduce the price per kit.
Erik van Vught, Goffin Molecular Technologies
Mr van Vught said that a kit should not cost more than 10€, as determined by the market, or perhaps 12€ if the test is very unique. This price should include the costs of distibution and logistics. However, doing distribution ourselves would jeopardize the value creation out of our sales. Therefore, it is recommended to outsource distribution.
Dr Dam, Medical doctor
Dr. Dam told us that in The Netherlands tests for this pandemic were paid by the government. For other infectious diseases, the tests are paid by health insurance companies.
Dr Heleen Koudijs, Tropical doctor
In order to get the cost of the kit low, Dr. Koudijs told us it is important to follow the guidelines of UNESCO, UNICEF, WHO and other NGO's. For many lower-income countries, these organizations fund the purchase of diagnostic tests. In other countries, like Ethiopia, the government pays for medical devices.
Dr Sophie van Baalen, Researcher team medical technology for Rathenau institute
Dr. Van Baalen also suggested thinking about strategies to ensure equal distribution during a pandemic. For example by adopting a model in which high-income countries would pay a higher price for test-kits than lower-income countries.
Integration
In a pandemic where the entire world is affected, everyone should have access to diagnosis. However, everything has a price, and a business cannot continue to provide products without income. Diagnostics should be sold at a very low price as usually they are government-funded, but sometimes also by foundations and NGOs. Therefore, businesses have to work with an immuable, limited budget. An economical test would allow governments to be able to test more, and repeatedly.
An advantage of molecular diagnostics is that they tend to be rather economical. Our team tried to approximate the cost of a single test reaction performed in the lab. The cost of a single detection (as determined by the purchase cost of the reagents, sequences, buffers, and enzymes) was around $1.45, without the hardware (as determined on our Proof of Concept page). If the kit is mass-produced, this price can be lowered even further.
Our team felt that the cost of a kit should not limit the access to diagnostic devices. We therefore plan to implement a self-sustaining hybrid economic system to make our kits affordable. In this hybrid model, the price of the tests would depend on the income of the countries. High income countries, would then pay a "premium" price that would co-fund the purchase of tests by NGOs or governments in lower income countries.
Question: How can kits reach our kits reach the target population? How can they be distributed accordingly?
Input
It is probably rather easy for an inhabitant of high-income countries to get tested for a particular disease. However, for certain regions, it can be a true challenge to reach a target population 9. Therefore, our team has asked experts which challenge should be overcome to reach the populations that can benefit most from our development. This entails research on regulations but also some logistical aspects of distribution.
Regulations
Qserve
Qserve is a consultant company that helps diagnostic companies to get a CE label from the notified bodies. There are two notified bodies in the Netherlands, Dekra inc. and BSI. A CE label is proof that a product conforms to the European regulation and is therefore essential when bringing a product to the European market. The EU regulation our kit needs to abide by, in order to obtain the CE marking, is the In Vitro Diagnostic Regulation 2017/746. The notified bodies test our kit independently to ensure that our kit abides by the regulation.
Erik van Vught, Goffin Molecular Technologies
When trying to receive approval to sell our kit overseas, Mr van Vught suggested to first market the product in our own country, the Netherlands, as it is one of the leading countries in (molecular) diagnostics, therefore also the most critical market. If it works in the Netherlands, we would be more comfortable selling it in other countries.
René Paulussen, managing director Mondial Diagnostics
Outsourcing or licensing a part of our business to large companies is the optimal for bringing our kit on a foreign market as they have a great sales and distribution network and often have contacts with regulatory bodies or government members. The latter is important as good relations with the local government facilitates the approval and implementation of the devices.
Ward Heij, Monitor Deloitte
Ward Heij told us that there is a difference between public and private markets. Procurement for public healthcare is often centralized either on a national or regional level. Sometimes, smaller consortia of hospitals procure together. It is rare that individual hospitals procure for themselves. Additionally, procurement is often done through tendering. It is also important to remember that due to price competition, better quality is not necessarily sought after. Often, the cheapest product that matches all certifications is sold.
Guus Eskens, Retired researcher and CEO of CARE Nederland
Guus shared with us some of his extensive experience with CARE Netherlands, Cordaid, IDA Foundation, and years of living in Africa. He provided us with insight into the state of the market for diagnostics and therapeutics in Africa. In certain countries, the major players in the medical field are international NGOs, often financed by large funds or wealthier countries. These NGOs work with funding programs (or missions), where they address a single crisis situation. The equipment and drugs are purchased depending on the goods that have been certified, tested, and approved by large bodies such as the FDA and the WHO. The equipment is then imported into the area in need. In a crisis situation, the complicated and delocalized logistics, may cause an inevitable administrative delay in bringing a novel product from the lab to the field. Therefore, to get into this market, the kits have to be approved by the larger bodies. The idea of modularity is interesting, but it will never be approved by these bodies if the tests are modular. As a consequence, the immediate, "rapid response" to epidemics is not fully achievable.
Distribution/Logistics
René Paulussen, managing director Mondial Diagnostics
According to Mr. Paulussen, distribution is always a challenge. However, the difficulty lies in getting our kit approved in the countries where we want to sell. Once we get our approval first, then the distributors will come.
Dr Otto Kroesen, researcher of cross-cultural entrepreneurship for development
Dr. Kroesen also proposed that (a part of) the production could be done in Africa. He gave South Africa as an example to do packaging in. However, it is definitely important to take into account what the benefits are of moving production to Africa.
René Paulussen, managing director Mondial Diagnostics
Distribution in Sub-Saharan Africa happens on trucks driving through the desert. The temperature inside these trucks can exceed 55°C. Therefore, it is essential that the kits are robust and can withstand these extreme temperatures.
Dr Heleen Koudijs, Tropical doctor
Dr Koudijs told us that in Ethiopia RDTs are distributed in distribution centers (mostly from UNICEF) on scooters on walking paths to the remote villages.
John Tonkinson, DCN DX
Mr. Tonkinson suggested making a kit with the least plastic possible, small and compact, which would be easier for transport.
Guus Eskens, Retired researcher and CEO CARE Nederland
Mr. Eskens told us that the conditions for logistics and distribution in certain remote places, like on the African continent, can vary greatly. These variations can complicate the distribution in certain regions. The availability and reliability of electricity can compromise the cold transport chain and the very long distances between regions yield high distribution costs. The temperature in containers left in harbors without a cooling system can reach 60-70°C. Their unreliability can be a problem to safeguard the quality of the tests.
Integration
Regulations
Understanding the regulations that govern the market of diagnostic devices globally is important. Experts helped us understand what it takes to bring a kit to a market where the standards are extremely high, versus a market where low(er) cost applications are often the norm.
Indeed, in high-income countries, the governments make up stocks of basic medical necessities. Therefore, the products have to be tested and approved by the notified bodies (such as the CE marking). In contrast, in lower income countries, large NGOs fund these medical supplies and are funded by foundations. They purchase these based on recommendations from bodies like the WHO. Therefore, kits first have to be tested and approved and gain a reputation on the market. However, there is a risk that modular kits might not reach the target users as quickly as initially intended due to inevitable administrative delay. Yet the nature of our kit (pre-produced generic part) could help in reducing this delay in an epidemic setting.
From a business perspective, it is complicated to market and commercialize a modular kit that cannot be tested immediately. Therefore, our team has become aware that we have to start small and gradually build up the product to its final, modular application. By focussing on the group of respiratory-borne RNA viruses, our kit could already be applied and tested for specific diseases like influenza. If we prove that the kits respond to the requirements for specific diseases (sensitivity, accuracy, speed), it can increase the credibility of our modular application, build up a reputation and accelerate their approval and implementation in a crisis situation.
Distribution/Logistics
In lower-income countries, including many countries on the African continent, transport and logistics are often difficult for complex, bulky, fragile, refrigerated medical devices. Therefore, robustness and temperature insensitivity are the qualities sought after in a kit. Additionally, the distribution costs in more isolated regions can be very elevated. As a consequence, the regions where these kits are highly needed are eventually poorly covered in the required medical supplies.
The majority of the reagents in the Rapidemic test kits can be freeze-dried, which can respond to the need for better conservation and subsequent long-term storage and distribution of the products. We predict that this could also render the reagents more resistant to high temperatures 10. Additionally, as we are aiming to design the embedding of the test reagents in a simple, robust device, this will likely require less specialized distribution systems.
The exact hardware of the kits has not yet been detemined. However, given that very little volume of the reagents is necessary, the kits could be made in a very compact format. Our team has even considered doing a paper-based test. This will also facilitiate the distribution of the tests.
Question: How can we make ensure that our kit is disposed of in a safely manner?
Input
As mentioned in "Users and user friendliness", the best way to make sure that the kit is properly disposed of is by entrusting trained professionals with the use of the kit. In the Netherlands, the hospitals are responsible for managing their own waste. How can we ensure that the used kits present no environmental or health risk whatsoever, in the Netherlands and abroad? Which waste category would used kits qualify as?
Dr Armand Paauw, Scientist at TNO Defence, Security and Safety, & Dr Hans van Leeuwen, Senior Scientist at TNO
According to the two scientists, our kit should be considered as contaminated hospital waste and should be disposed of accordingly. They also said that in order to inactivate the pathogens, the samples should be lysed entirely, which would render the pathogens harmless. This can be achieved with a lysis buffer, for instance. However, they suggested testing whether the pathogens are effectively neutralized and that a lysisbuffer is sufficient to do so. Alternatively, they told us that the samples could be inactivated by steaming them for 10 minutes at 80°C before disposal.
Waste transporting company
Bram de Graaf, Project Manager hazardous waste NNRD
The NNRD is a waste transporting company responsible for the waste collection and transport for the areas Drachten and Groningen. All the waste transporting companies in the Netherlands follow the regulations from the ADR. The driver has to have an ADR diploma and the truck has to be ADR certified as well. After the waste is collected from the hospitals, the waste is dropped brought to the depot until there is enough waste to be transported to the waste disposal company Zavin in Dordrecht.
Waste disposal company
Ron Roffel, Operational director Zavin
According to Mr. Roffel, the hospital staff in the Netherlands is rather considerate of waste separation and disposal infrastructure. However, he said that Dutch general practitioners sometimes fail to separate their medical waste correctly, yet this is improving. According to Mr. Roffel, if the waste disposal of point-of-care kits is left to the general public (patients), proper separation of the medical waste is practically unachievable.
We also learned from this visit that the majority of medical waste worldwide is improperly disposed of, even in Europe. In a best-case scenario, all the medical waste is incinerated in the open air. In worse conditions, the kit may end up in an open landfill or in nature. In the latter case, the kit should be hermetically sealed off and non-hazardous, to ensure it does not present a health threat to the population.
To read more about our visit to Zavin: Click here!
The future of waste diposal
Gerard Vincent, CEO Red Bag Solutions Europe
Red bag solutions is an alternative option for medical waste disposal in the Netherlands. Instead of incineration, they use water sterilization. The benefits of their technique are mainly environmental. They can reuse up to 95% of all their materials. This tech also saves up almost 100% of nitrogen and 75% of CO2 from medical waste.
Waste disposal in Africa and Asia
Dr Heleen Koudijs, Tropical doctor
According to Dr. Koudijs, the waste in Ethiopia is thrown on top of a pile until the pile is big enough to be incinerated out in the open. However, the situation in hospitals is better. Hazardous waste in hospitals in Ethiopia is well separated. It is very unclear how the waste is separated and processed in countries like Zambia and Tanzania.
Dr Assica Permata, M.D. currently working on TB in a research environment
Dr. Permata shared with us how infectious waste is handled in Indonesia. One of the anecdotes that stuck with us is the fact that some doctors expose contaminated material to sunlight for sterilization. The remaining waste is disposed of in bags and likely burned.
Integration
Through contact with the diagnostic companies, we have rapidly understood that RDT developers do not integrate the end-of-life considerations, such as environmental or (health) safety, into the developmental stages of the products. We also realized that developing a medical product for low-resource countries with inadequate infrastructure can present certain risks, that should be taken into account in the design process. Therefore, we contacted professionals in the field to understand how our team could consider and integrate these considerations into our project, even at a very early stage.
After our kit has been used, it will be classified as hospital waste and should therefore be treated as such. In the Netherlands, the quality of the disposal systems in place is not perfect, yet the country it is among the best in the world. Just a few countries further, the quality of the waste treatment is drastically worse or even non-existent 11. The disposed medical waste is landfilled, mixed with regular house waste, or incinerated without post-treatment of the fumes.
There is a common tendency regarding waste disposal across the world. If not landfilled, everything is often incinerated. Therefore, given the material is not recycled, nor left to degrade, there is less environmental value in making our test kits from degradable material (with harmless contents), such as biodegradable plastics. One way to decrease the impact of the kits would be to use recycled content to reduce the unnecessary incineration of virgin material. However, opting for recycled materials sometimes also entails decreased polymer quality and therefore reduced robustness. Therefore, it is important that the quality of the qualitative output is maintained and that the kits are robust.
Additionally, if the kits are incinerated, all the potentially infectious material, which should already be lysed, is killed. Instead, if the hospital waste is placed in a landfill to which the population has access, the content of the kits could present a risk. Therefore, the potentially infectious material should be lysed. The chemicals contained in the kit cannot cause any serious harm, yet to ensure maximum safety, the kits should no longer be opened after use.
Question: What social considerations do we need to take into account when doing business in different areas of the world?
Input
Doing business in Africa is certainly not the same as doing business in Europe. Topics like culture, social taboos, trust and extreme poverty all play a significant role in determining if our product is going to be a success or a failure.
Dr Heleen Koudijs, Tropical doctor
A significant portion of the Ethiopian population lives in extreme poverty. This means many people in Ethiopia earn less than one euro per day. Therefore, taking a day off to test has severe consequences for the families. Testing in Ethiopia is regulated and performed by the Ethiopian government. The patients are tested and then put into isolation (quarantine) until the results are in. If the result of the test is positive then they are isolated two more weeks, if not then they are free to go. This has severe financial consequences for the families involved. Another cultural consideration is that Ethiopians will probably not wait long to get the test result. According to Dr Koudijs, keeping people in hospitals was, therefore, quite the issue. To combat this, it is recommended to have a kit that has a test result within two hours. Lastly, having a disease (like HIV, for instance) in countries like Kenia is a big social taboo. Privacy is therefore crucial and should not be neglected.
Dr Otto Kroesen, researcher in cross-cultural entrepreneurship for development
According to Dr. Kroesen, there is very little trust in shop owners. Even physicians are not always trusted. If the kits are given to health workers for free then there is a good chance that kits will go missing. However, for any transaction, it is important to have the trust of the locals. It is also important to have kits handled by trustworthy people. Trust can be earned through schools and churches. However, it does take a lot of time to gain trust.
Integration
Social considerations should not be forgotten when trying to enter the African market. Gaining trust is of vital importance. The best strategy regarding the quickest entry into the market is licensing our product to a company with a good reputation and which is trusted by the local population. The social considerations regarding the feeling of being looked down upon and the social taboo related to a disease (like HIV) are struggles that are mainly affecting the physicians. Therefore, these issues cannot be solved by an RDT since these issues are cultural. The fact that people are not willing to wait is problematic. Fortunately, this issue can be (partially) solved by having shorter (less than 2 hours) reaction times.
References
- MacIntyre, C., & Chughtai, A. (2015, December 19). Recurrence and reinfection-a new paradigm for the management of Ebola virus disease. Retrieved, from https://www.sciencedirect.com/science/article/pii/S1201971215002921?via=ihub
- Who.int. 2020. Yellow Fever. [online] Available at: https://www.who.int/news-room/fact-sheets/detail/yellow-fever
- Who.int. 2020. Dengue And Severe Dengue. [online] Available at: https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue
- McNerney, R. (2015). Diagnostics for developing countries. Diagnostics, 5(2), 200-209.
- R.W. Peeling, D. Mabey, Point-of-care tests for diagnosing infections in the developing world, Clinical Microbiology and Infection, Volume 16, Issue 8, 2010, Pages 1062-1069, ISSN 1198-743X, https://doi.org/10.1111/j.1469-0691.2010.03279.x.
- Liao, A. M., Pan, W., Benson, J. C., Wong, A. D., Rose, B. J., & Caltagirone, G. T. (2018). A Simple Colorimetric System for Detecting Target Antigens by a Three-Stage Signal Transformation–Amplification Strategy. Biochemistry, 57(34), 5117-5126.
- Bendavid E, Ottersen T, Peilong L, et al. Development Assistance for Health. In: Jamison DT, Gelband H, Horton S, et al., editors. Disease Control Priorities: Improving Health and Reducing Poverty. 3rd edition. Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2017 Nov 27. Chapter 16. Available from: https://www.ncbi.nlm.nih.gov/books/NBK525305/ doi: 10.1596/978-1-4648-0527-1_ch16
- Lobato, I. M., & O'Sullivan, C. K. (2018). Recombinase polymerase amplification: basics, applications and recent advances. Trac Trends in analytical chemistry, 98, 19-35.
- Katoba, J., Kuupiel, D., & Mashamba-Thompson, T. P. (2019). Toward Improving Accessibility of Point-of-Care Diagnostic Services for Maternal and Child Health in Low- and Middle-Income Countries. Point of care, 18(1), 17–25. https://doi.org/10.1097/POC.0000000000000180
- Park, H., Kim J. U.S. Patent 6,153,412, 2000
- Wajs, Jan & Bochniak, Roksana & Golabek, Aleksandra. (2019). Proposal of a Mobile Medical Waste Incinerator with Application of Automatic Waste Feeder and Heat Recovery System as a Novelty in Poland. Sustainability. 11. 4980. 10.3390/su11184980.
In a holistic concern about the safety aspects of our kit, our team was wondering where medical devices like Rapidemic would end up after use, and whether the end-of-life could pose a threat to a population group. Members of our team had the opportunity to visit the Dutch national medical waste treatment plant, Zavin, in Dordrecht (NL), with the hope to obtain some answers to our questions. We also sat down with the head of operations, Ron Roffel and exchanged ideas and doubts about our project. Yearly, the company processes 10 000 tons of medical waste from the entire country and is expected to process 12 200 tons next year. This is way over their capacity and has therefore made a partnership with a Belgian waste treatment company. Zavin was originally designed to dispose of 6000 tons per year.
Zavin Operations
Incinceration is still a golden standard for high throughput and safe management of medical waste management. More local waste management options are autoclavation and subsequent separation and landfilling, or the Pharmafilter technology, which enables breakdown of biomaterials. "Medical waste" comprises used needles, vaccines, antibiotica, hormones, genetically modified organisms, protective gear or tissue samples, or any material that may have been in contact with potentially infected patients. However, the definition may vary regionally.
In the Netherlands, this waste is disposed off in blue or grey (90% recycled content) platic bins, specially designed for the company that are hermetically sealed off on-site and picked up by large waste companies. About 3 to 6% of the total hospital waste generated is sent to Zavin. The bins are brought to Zavin, where the bins are deposited on a conveyer belt to the incinerator where they are burnt at 850-1100°C in their entirety. This way, workers are not exposed to any health risks due to contact with the dangerous waste. The waste is burnt by a pretreatment oven (850 centigrade) and the oven (1100 centigrade). The remains are transported upwards for cooling and then put in a water bath while the waste that was not sufficiently desintegrated is sorted and subjected to another round of incineration. The toxic gasses that are generated are burned in the post-treatment oven at 1200 centigrade and carefully monitored. Whilst cooling down, the gas is then further purified using an extraction column (the gas is purified by passing through water). Brown coal cokes pellets and a 18% NH3 solution is also put into the post-treatment to reduce emissions, the latter to reduce NOx emissions. The remaining product, called slack, is then transported for landfilling.
Legally, it is not allowed the recover any energy or materials from medical waste, as it is considered dangerous. However, Zavin recovers energy from the burning process to sustain their activities and some of the other companies on the Dordrecht Industrial Parc. For example, they collect their steam and transport it to their neighbours HVC to be used in their turbine. When compared to other methods, incineration is considered to be a rather sustainable option for medical waste processing. Autoclaving still requires large amounts of energy but also intensive labor for subsequent sorting or polluting landfilling. Another downside of autoclaving is that the product will still eventually be incinerated at the end of its life, which begs the question if the autoclaving option is pure for economics.
And Beyond?
The Netherlands and surrounding West European countries like Belgium and Germany have similar waste treatment processes. However, medical waste from small medical practices, but more importantly from general practitioners or even individuals is not always disposed off properly (as dangerous and contaminated waste), and can end up in the waste streams for regular household waste. This is due to the fact that laws and regulations for businesses and organizations are more vigorously reinforced than for individuals. Pregnancy tests, antibiotics and other medicines, syringes and other medical waste disposed by the latter are therefore processed in a manner than can pose a real threat for workers. Nonetheless, these are countries where the systems and regulations in place are rather efficient, and they are the rare few. Indeed, the vast majority of countries do not have such waste collection systems in place. Medical waste is then disposed off and treated inasmuch the facilities present can enable and sustain it. This can be, (informal) landfilling or backyard incineration. In some countries, it is not unusual to see children play in heaps of mixed waste, which poses a very serious health risk for the communities.
Responsibility
Companies in the field of medical devices are making efforts towards increasing the accessibility of tests and their ease-of-use, for instance, by developing self-tests. Through contacting various business stakeholders, we have understood that developers do not actively reflect on the end-of-life of their products nor adopt an integrated, holistic attitude or an anticipative approach in the product development process. Indeed, businesses do not take on the responsibility for potential safety or the environmental risks that might occur after the product has exited the factory gates.
Regulations on (medical) waste differ regionally or nationally, sometimes further complicated by a dubious/ debatable implementation. As a consequence, even when these regulations are enforced, the waste may still present risks for communities (as seen for the NL). As a consequence, we truly believe that the responsibility for ensuring the safety of medical devices lies with the manufacturer, and the latter should integrate these, regardless of the theoretical regulations set in the intended geographical share of its market. This is why in this project, we actively aimed to address all the hazards that can arise along with the lifespan of a single device when commercialized even in the most isolated or less developed areas of the world.
