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Chapter 1.1. Translating research for the people: Development of affordable rapid diagnostics for low-resource countries

Authors: 

Asma Ismail

Art work
Title: 
Malaria
So, I can't show you how, exactly, health care is a basic human right.
 But what I can argue is that no one should have to die of a disease
 that is treatable. Paul Farmer
I prefer myself liking people
to myself loving mankind
Wislawa Szymborska
Possibilities. 

Introduction

The first step towards controlling an outbreak is to carry out investigative diagnostics to find infected individuals so as to provide treatment. Owing to the large demand, it is not surprising that the world market for in vitro diagnostics was approximately USD 30 billion in 2000, with nearly 50% of procedures based on biotechnology [1]. With regard to diagnostics, rapid tests (dipsticks) account for USD 9.5 million, whereas approximately USD 3 billion is spent on diagnostics based on monoclonal antibodies (mAbs) [1].

Nucleic acid-based testing accounts for 30%, or USD 9 billion, of the diagnostics market (> 1,000 times that spent on rapid tests). The predicted growth rate of this market is approximately 20%. It has been predicted that molecular diagnostics and genomics will see the greatest growth over the next 5–10 years. The diagnostic market has the fastest growth rate because it is characterized by rapid development turnaround, few regulatory barriers, and competitive production costs.

Despite the variety of diagnostics available, annually, 1 million people die from malaria, 4.3 million from acute respiratory infections, and 5 million from AIDS or tuberculosis, especially in underdeveloped or developing countries [2]. Many more will continue to die annually because adequate diagnostics are inaccessible in underdeveloped or developing countries. Most of the current diagnostics available do not focus on the diagnostic needs of the poorer countries of the world. The unavailability of these diagnostics has greatly affected healthcare delivery in low-resource countries. Without reliable diagnostics, healthcare personnel are making diagnoses by observing patient symptoms. Although this may not be the best method, it is a reality in these parts of the world. Unreliable diagnoses leads to ineffective treatment due to the inappropriate use of antibiotics, which eventually leads to drug resistance. In a borderless world with high cross-border travel and migration, ineffective treatment not only endangers the lives of patients but also becomes the source of epidemics with high rates of transmission and antibiotic resistance.

The diagnostic problems associated with low-resource countries are no longer restricted to those countries but have become a global problem that needs to be addressed. Hence, it is imperative that diagnostics development should concentrate on the technical requirements and criteria for use against diseases of burden in low-resource countries [3, 4].

Types of diagnostics

Diagnostics can be classed into the following categories:

  • Investigative diagnostics to identify infected individuals and provide a guide to treatment, thereby preventing drug resistance
  • Epidemiological diagnostics to investigate the extent of the disease in the population
  • Pharmacogenomics diagnostics to guide local clinical trials to determine if a particular drug is suitable for certain races in a certain locality
  • Genotyping diagnostics to predict if someone will develop a disease and hence prevent it

Problems with the current diagnostic scenario

Despite experiencing decades of epidemics, we still do not have an adequate number of diagnostic tests. This could be owing to the lack of emphasis placed by grant funders on the diagnostic development agenda. Diagnostics continues to occupy a small proportion of healthcare budgets compared with drugs. For example, the European Union (EU) research grant scheme (2002–2006) allocated only 3% of the budget for diagnostics research compared with 49% for treatment and prophylactic research [2].

This lack of emphasis on diagnostics is becoming increasingly apparent, despite advances in technology; tuberculosis (TB) is still diagnosed by microscopic examination of sputum (with only 40–60% sensitivity), and takes 6 weeks to produce culture results [2].

Moreover, current diagnostics do not address the needs of developing and/or underdeveloped countries. In such situations, even if the diagnostics exist, they are ill adapted for countries that lack trained personnel and infrastructure. There seems to be a paucity of product developers and designers who truly understand the need for diagnostics for people in low-resource settings. This deficiency in underdeveloped countries could also be due to the lack of pioneering researchers with sufficient training to translate research from the laboratory to industry.

Hence, it is imperative that local researchers in poorly resourced countries receive the training necessary to develop innovative diagnostics that address the needs of low-resource settings. This would allow them to play a major role in the development and design of diagnostics that are relevant to the region, because the challenges faced in such situations are best understood by local researchers. Eventually, researchers among the neglected population must be taught to help themselves to ensure the sustainability of the healthcare delivery system in their own country and in the region as a whole.

This would imply that diagnostics should be designed to have an impact on healthcare by making it accessible to the people who need it most. To assist the diagnostic industry in catering for the neglected population, diagnostics must be designed and developed according to the World Health Organization (WHO) ASSURED criteria for primary healthcare settings [5]. Therefore, diagnostics must be:

  • Affordable
  • Sensitive
  • Specific
  • User-friendly (simple to read and interpret, and useable by minimally trained personnel)
  • Rapid and robust (capable of functioning above 30°C and at high humidity)
  • Equipment-free (allowing personnel to conduct tests without the need for specialized reagents and equipment)
  • Deliverable to end-users (capable of being transported and stored without the need for refrigeration).

The challenge to create ASSURED diagnostics is more critical for nucleic acid-based tests because the development of point-of-care tests for DNA diagnosis is still in its infancy. The technology requirements would include appropriate integration of sample preparation to produce high-yield nucleic acids with minimal inhibitory effects, DNA amplification without the use of expensive machines, and detection via the naked eye.

Creating diagnostics for low-resource settings

Infection constitutes the major disease burden in less developed countries. Infectious diarrhea-causing diseases such as typhoid, paratyphoid, cholera, and dysentery are the second biggest cause of morbidity and mortality worldwide, accounting for an estimated 3,100,000 deaths annually [6, 7]. Every year, WHO estimates that millions of people, mainly the elderly, infants, and children, suffer and die [8]. Food- and waterborne diseases contribute substantially to the mortality and morbidity of humans, and are related to unhygienic environments and habits. Such diseases are transmitted by direct or indirect contact with fecal matter, or fecal contamination of food or water [9]. Typhoid, paratyphoid fever, and dysentery are among the enteric diseases that remain a global public health problem, especially in Third World countries, or in what is known as the forgotten bottom billion [8].

The mortality rate is further elevated in the event of natural disasters or war. Hence, in the spirit of health for all, there is a need to reduce inequity and create original diagnostics that are suitable for low-resource settings and are accessible and affordable to those who need them most.

The improvement of sanitary conditions and hygiene would be the route of choice to address these problems, but developing countries do not realistically have the means to adopt this approach. Increasing antimicrobial resistance and the lack of prophylactic vaccines have created hurdles in disease control. Vaccines for typhoid are available but are not effective. Vaccines for shigellosis are not available outside China, and none as yet is available for Salmonella enterica Paratyphi.

Existing diagnostics are also lacking for the detection of carriers who serve as reservoirs for the spread of disease. This calls for an increased effort in the development of both diagnostic tests and vaccines for combating diseases. Rapid diagnosis can contribute to early and effective management of disease. Once carriers have been identified, the organisms isolated from them can provide an understanding of the epidemiology of a disease, which can be used to prevent it.

Formulating research design for diagnostics in low resource settings

If research products are to be accessible to the community, there is a need to bring the results of research from the laboratory to industry. To be accessible to the majority of clients globally, the diagnostic kits that have been developed must be commercialized.

To ensure the commercial viability and sustainability of diagnostics for Third World countries, research needs to be carried out with the client in mind. This would ensure that the product is relevant, would help reduce inequity, and would make quality products accessible and affordable. The delivery of people-led solutions requires a paradigm shift in the approach to research, starting with the client’s needs and working backwards to the experimental design. In simple terms, the approach is to work from Z (client needs) to A (experimental design), rather than the conventional approach of A to Z. In this approach, relevance to peoples’ needs takes precedence over technology- or market-driven solutions. In fact, the research and innovation challenge posed would be to develop currently nonexistent technology platforms that would satisfy the ASSURED criteria for diagnostics in low-resource settings.

New technology platforms must be created for diagnostics in areas where the water supply is unclean, the infrastructure does not exist or is minimal, there is a lack of electricity, a lack of refrigeration for transport and storage, or the personnel are unskilled. Other challenges include the reporting of results without need for sophisticated laboratory equipment. When developing diagnostics for underdeveloped or low-resource countries, it is imperative that the design criteria include sustainable values such as availability, accessibility, affordability, quality, and relevance to the people who need them most. It is also important to note that diagnostics made for Asian needs might also be required by African and Latin American markets. From a marketing perspective, diagnostics that address the problems of Asian and Third World countries have high predicted sales volumes, because half the world’s population is located within these regions. The solutions offered should be useful locally as well as globally.

Translating for the people: The USM experience

Universiti Sains Malaysia (USM) has a mission to ensure that its research and innovation outputs are practical solutions that can help reduce inequity and effectively benefit the Malaysian community. The solutions provided should also be globally relevant to help the neglected populations in low-resource countries. To achieve this, USM must establish its presence and leadership in the global research community, but at the same time must champion R&D-backed innovations that are suitable for low-resource settings.

When the Nobel Laureate Ahmed Zewail first visited Malaysia as the Scientific Advisor to the country, he advised that “If you work on research topics that the West is not interested in, you will always be 20 years ahead. If you work on topics that the West is interested in, you will always be 20 years behind.” This advice inspired what is now known as the Blue Ocean Strategy [10], and was used by USM to determine its research direction and boldly explore markets with little competition. In the field of diagnostics, the Blue Ocean Strategy has been used to develop diagnostics against infectious diseases and make them accessible and available to people in low-resource countries, where more than half the world’s population is located. The challenge will be to develop new technologies to meet diagnostic requirements, and at an early stage of conception, adopt research methodology and experimental designs with the targeted client in mind. High-prevalence diseases translate into high sales volumes, making the new technologies attractive to venture capitalists hoping to invest for commercial purposes.

The rapid diagnostic research cluster at the Institute for Research in Molecular Medicine (INFORMM), USM, is at the heart of the medical biotechnology group in the university as well as in the country. The cluster accepted the research challenge of providing diagnostic solutions to the problems caused by the infectious and tropical diseases faced by Malaysia and her neighbors. Guided by the WHO ASSURED criteria, the research cluster chose to strategically and systematically develop diagnostics for use against typhoid and paratyphoid (for the detection of acute cases and carriers), filariasis, campylobacteriosis, tuberculosis, cholera, and shigellosis. These diseases were chosen because few, if any, competitors are developing diagnostics to use against them.

The research cluster focused on the creation of diagnostic tests that can be performed at point-of-care (both DNA-based and protein-based) to satisfy the criteria of rapidity, sensitivity, specificity, cost-effectiveness, and freedom from the necessity of a cold chain. Investments were made in the training, equipment, and dry room facilities necessary to produce point-of-care tests (protein- and DNA-based), which allowed INFORMM to design, develop, and produce the prototypes needed for testing and field trials (Figure 1). Hands-on experience, skills, and knowledge of test design and development characterize the human resource working in INFORMM, which includes graduate students (local and international), so that this knowledge and skill can be used to provide solutions to other relevant disease problems in the regions where they originate. Exposure to the concept of social enterprise will move those involved a step closer to help bridge the gap of inequity and move science towards humanity.

       

Figure 1. Prototype development facilities for protein and DNA based dia

To extend the value of intellectual property rights, patents on scientific discoveries were filed separately from the technology platforms. In this way, the tests can be produced using the same scientific discoveries but developed with the relevant technology platforms required by the market in low-resource countries. To date, rapid test kits have been designed using innovative technology platforms such as dot enzyme immunoassay, enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction–enzyme-linked immunosorbent assay (PCR-ELISA), other PCR-based tests, immunochromatography (dipstick), and thermostabilized PCR tests. Because the future will depend on molecular diagnostics that deliver the best sensitivity and specificity, it is essential that similar molecular tests of quality be made available to the neglected population at low cost. The aim of the diagnostic team is to push the frontier of technology, improve sensitivity, and remove the necessity of equipment to make the tests more simple and user-friendly. The cluster’s latest developments include the combination of immunochromatography and thermostabilized PCR-based tests, thereby dispensing with agarose gels to visualize the PCR product [11, 12] (Figure 2).

Figure 2. Thermostabilised PCR-based tests uses immunochromatography to visualize the PCR product

The ultimate aim is to remove the need for a PCR machine altogether by producing easy-to-interpret non-PCR-based diagnostics so that tests can be conducted without a cold chain, and can be performed in the field without the need for skilled personnel or an electrical supply. Work is currently taking place to create indigenous nitrocellulose membranes [13-15], DNA amplification enzymes extracted from a Malaysian bio-resource [16], and indigenous monoclonals conjugated to indigenous gold [17] to further reduce the cost and make Malaysian products more competitive in the market. The development of these new reagents and membranes will also spur new bio-based Malaysian industries. These diagnostic products are being developed into prototypes to be evaluated nationally and internationally via multicenter trials in the various countries that are partners to the cluster.

The Blue Ocean Strategy has paved the way for the successful commercialization of the cluster. To date, six diagnostic kits have been commercialized at national and international markets, and more will be added to the list (Figure 3). The commercialized rapid diagnostic kits include an antibody detection kit for Salmonella typhi using a dot enzyme immunoassay (EIA) via TYPHIDOT (to detect specific IgM and IgG immunoglobulins), TYPHIDOT–M (to detect specific IgM), TyphiRapid-M (an immunochromatography test for the rapid detection of IgM due to S. typhi), and Brugia Rapid and Pan LF (rapid tests for filariasis) [18]. Whereas the filariasis test has only recently been commercialized, typhoid-based kits have been used in more than 18 countries around the world, and more than 2 million patients have benefited from them [9, 19-21]. Typhoid kits have also generated publications by authors who have studied the products [22, 23], and provided at least 500 jobs globally for distributors and workers in the pipeline. Because all the kits are sold in USD, they have contributed to Malaysia’s foreign exchange, spurred the country’s bio-diagnostic industry, and consolidated supporting industries (such as the packaging and bottling industries, and courier services).

Figure 3. Diagnostic kits produced by INFORMM

The high-quality, innovative diagnostic tests for low-resource settings produced by the rapid diagnostic cluster at INFORMM, USM, are an example of the diagnostic solutions offered by researchers who understand the problems faced by people in developing countries. Such researchers are driven by their passion to develop healthcare technologies that are capable of reducing inequity. Their efforts have resulted in national and international recognition for the University, including the prestigious Islamic Development Bank award for Science and Technology, awarded in 2008 for making a significant impact on Muslim countries and the neglected population. Individual efforts by the research scientists and the research team have been rewarded with numerous awards and recognition at national and international levels.

Accepting the diagnostic challenge posed by low-resource settings has brought phenomenal results to the diagnostic cluster at USM. The area of research is a gold mine because the work has resulted in patents and intellectual property rights, and the opportunity to ride the knowledge economy (K-economy) and observe the commercialization of R&D at close range. The cluster’s successes have motivated other scientists to dabble in the commercialization of R&D and have charted the course for Malaysian science to move from the laboratory to industry. Moreover, the cluster has brought presence and leadership to the global research community in the area of rapid diagnostics for the poor, and has contributed significantly to the country’s growing competence in this field.

Way forward: Catapulting sustainable diagnostics globally

The innovation economy

Competitiveness and national progress are based on the innovative performance of human capital and no longer based on skills [24]. It takes innovation to translate the combination of science, arts, and technological advances into more productive economic activity via products, services, and entrepreneurship. To create an innovation-led economy, a country needs to develop a society that embraces a culture of creativity and innovation, and human capital is the main driving force. The need for the political will to push for the creation of an innovative eco-system in a country is of utmost importance, and is especially critical in low-resource countries.

Bridging the gap

For low-resource countries to have sustainable economies, there is a need for strategic capacity building and technology acquisition so that such countries can help themselves. One way of sustaining strength is to collaborate to prevent economies collapsing in the future. Although much international research collaboration has occurred between low-resource countries and numerous strategic partners, thus far none has proceeded to the level of world-class knowledge-based industry that can support its economy, as is the case with Nokia in Finland or Samsung in South Korea. As stated previously, no one understands the market needs of neglected countries better than the people themselves do. By learning the technology, diagnostics can be created, improved, or customized to provide the innovative solutions needed by a country. Because the future market is Asia [25] the future world market must provide the needs of Asia, where half of the world’s poorest billion people are located. Satisfying their needs would create a good business platform for companies that can truly provide affordable diagnostics suitable for low-resource settings.

In terms of collaboration, there is a need to determine whether the decision to collaborate would be based on: (1) matching strengths; or (2) combining strengths and weaknesses so that an advanced group could train another group in order to promote capacity building. Both types of collaboration could be developed with the identified areas of focus. If we can get developing/underdeveloped countries to work together in areas commonly encountered in low-resource countries, such as the development of indigenous research platforms, capacity building, publications, and strategic links to enhance the commercialization of R&D products, they will have a higher competitive edge in the world market. When made available to people within the framework of social justice, people-led solutions may help to reduce inequity and move one step closer to making good health accessible to all.

Strategic efforts to reduce inequity and provide accessible and available diagnostics that address the needs of low-resource countries include:

  • Global collaboration with scientists in R&D and the design of protein- and DNA-based diagnostics for infectious diseases that particularly affect underdeveloped countries, and ensuring the availability, affordability, and accessibility of such diagnostics to those who need them most
  • Joint development and commercialization of diagnostics with partner countries
  • Training personnel in the use of such diagnostics where required, and empowering poor countries to attain health for all
  • Collaborating to acquire training and learn the concepts of entrepreneurship and a pioneering mindset to create a valued and relevant chain of diagnostics designed and developed to detect common diseases in the country concerned
  • Developing relevant diagnostic technology platforms to ensure affordability and sustainability as part of science for humanity.

The availability of such diagnostics is imperative to ensure quality healthcare delivery in low-resource countries and prevent the transmission of diseases, both in the country concerned and globally. Affordable quality diagnostics should no longer only serve low-resource countries but in the new economic downturn, it also makes sense to make them available globally.

References

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