Team:Thessaly/Entrepreneurship
ENTREPRENEURSHIP.
ODYSSEE is an in-field diagnostic test for Tuberculosis that has been developed by our team, iGEM Thessaly, consisting of 10 ambitious students. Our goal was to address the current needs in Tuberculosis (TB) diagnosis, proposing a new point of care test accessible to all people that do not have access to modern health facilities, without the need for special equipment or personnel.
Since the earliest stages of our project, we have been considering the commercial aspects of it. For this reason, we came in touch with various stakeholders, considering their role as potential customers. Among those, we interacted with the WHO Greece, National Public Health Organization (NPHO), Doctors of the world, Doctors without borders, and hospitals, including General University Hospital of Larissa. Afterwards, we created our own business plan explaining the way we managed to get funding for the continuation of our project. Finally, a SWOT analysis and a full time plan for the following 24 months were constructed, taking industry perspectives into account.
Problem Definition
Nowadays, diseases of povertyDiseases of poverty are diseases that are more prevalent in low-income populations. The WHO estimates that diseases associated with poverty account for 45 per cent of the disease burden in the poorest countries. Tuberculosis, malaria and HIV/AIDS, together account for nearly 18 per cent of the disease burden in the poorest countries [8] remain a major cause of mortality, illness and lack of economic progress. Each year, these diseases cause an estimated 6.4 million deaths and the loss of 316.2 million years of healthy and productive life globally. Measured by the numbers of people who die each year, Tuberculosis (TB) is one of the top 10 causes of death worldwide. In 2014, for the first time in decades, TB killed more people than any other infectious disease in the world [1]. In patients with active TBThere are two types of TB; active TB, when the patient is infected by Mycobacterium, and latent TB, in which case the patient carries the Mycobacterium without developing the symptoms of an active disease [1]., Mycobacterium tuberculosis multiplies in different parts of the body. The symptoms of active TB disease include cough, weakness, weight loss, fever, loss of appetite, and night sweats.
Every year, approximately one in three who fall ill with TB are left undiagnosed or not registered by health systems. These “missed” 3.6 million people is the primary cause for the persistent high levels of TB transmission [1]. The reasons for this, are the low sensitivity of conventional diagnostic methods (e.g. smear microscopy) together with the high demands regarding infrastructure when using more sensitive molecular methods [2]. Without new drugs, diagnostics, and an effective vaccine, we will not achieve the reduction in incidence and mortality that we need, and millions of more people will suffer from the disease [1]. The current very limited investments in TB research and development have left the TB community to fight the disease with obsolete and inadequate tools.
Stakeholders Analysis
For a product to be established in the market, the opinion of crucial stakeholders should be considered, in order to ensure that their needs are met. For this reason, we conducted a stakeholder’s analysis, considering their interest and power at the same time.
Image 1. Interest/Power stakeholders analysis
Market Analysis
To identify customer’s needs and demands, we should first analyze all the segments and different aspects of TB market, in order to build a sound business strategy for ODYSSEE. Through the market analysis process, we were able to identify not only the environment and the regulatory system that ODYSSEE is going to be launching into, but also the competition that it is going to face.
Based on the geographic segmentation, Tuberculosis affects the entire world, causing a great economic loss for every country. The 30 high TB burden countries accounted for 87% of all estimated incident cases worldwide, and eight of these countries accounted for two thirds of the global total: India (27%), China (9%), Indonesia (8%), the Philippines (6%), Pakistan (5%), Nigeria (4%), Bangladesh (4%) and South Africa (3%) [3]. Greece is not included in the 30 high TB burden countries, with 467 TB cases in 2017, according to WHO. However, Greece is the crossroad of three continents; Africa, Asia and Europe, receiving people from different countries with different rates of TB. For this reason, ODYSSEE would not only be a helpful tool for Greece, but also for every country lacking specialized equipment, trained personnel, and health infrastructures (like hospitals) that need a rapid test for simple and fast TB screening.
Except from the lives lost from Tuberculosis, there is also a great economic loss caused by multiple factors. There are a lot of components which constitute the total cost per TB case, including the duration of hospitalization and inpatient cost per day, outpatient cost, cost of medication, and last but not least, the cost due to loss of productivity. Combining these direct and indirect costs, an average per-TB case costs in EU €10.282 for drug-susceptible TB, €57.213 for multidrug resistant (MDR)-TB and €170.744 for extensively drug resistant (XDR)-TB [4]. With ODYSSEE this cost could be reduced since it is more affordable compared to traditional diagnostics and easily associable to any circumstances, increasing the chances of decreasing the diagnostic gap and the losses (financial and non-financial) that stem from it.
Image 2. Estimated TB rates, 2017 [3].
Investments concerning TB
The Stop TB Partnership’s Global Plan to End TB, 2016–2020a (the Global Plan), is a 5-year investment plan that represents the roadmap to accelerating impact on the TB epidemic and reaching the targets of WHO's End TB Strategy. The Global Plan estimated that, in low- and middle-income countries, US $ 10.4 billion were required in 2018, increasing to US$ 12.3 billion in 2020. Based on data reported to WHO by 119 low- and middle-income countries with 97% of the world’s notified TB cases, US$ 6.9 billion was available for TB prevention, diagnosis and treatment in 2018, representing a shortfall of US$ 3.5 billion. Of the total of US$ 6.9 billion available in 2018, US$ 4.8 billion (69%) is for diagnosis and treatment of drug-susceptible TB and US$ 9 billion needed to fund research and product development (R&D) for new tools - including diagnosis, drugs, drug regimens and vaccines for these five years [3].
Global funding for basic Research and product Development (R&D) for neglected diseases in 2017 was $3,566m, the highest level ever recorded by the G-FINDER survey. Tuberculosis (together with HIV and Malaria) considered as previously neglected disease and continues to receive the majority of funds given. As previous years Tuberculosis, collectively with HIV/AIDS and malaria, received more than two thirds ($2,496m, 70%) of all global funding for neglected disease R&D in 2017. More specifically, 17% of global R&D funding, which reflects to 615m, was invested for Tuberculosis. If we take a dive into the TB R&D funds, we will see that 25% of these investments are for basic research and 11% for diagnostics, these percentages correspond to $155m and $68m respectively [5].
In Greece, there are no available data about investments in TB research and new product development. Generally, expenditure on R&D in Greece in 2017 was 2,033 million euros, 15.9% higher compared to 2016. The largest amount of the sources from which the 2017 R&D expenditure was financed, EUR 910.6 million (44.8% of total), came from businesses, followed by the Government, private non-profit institutions, and from abroad. The bulk, € 834.3 million, was invested in R&D carried out by the companies (BES) themselves. The remainder funded R&D in Higher Education (HES) (€ 48.1 million), in the public sector (GOV) (€ 25.2 million), and in private non-profit institutions (PNP) (€ 3.0 million) [6]. So, there are funds that could be invested in a new diagnostic test considering the socioeconomic impact of such a product.
Competitors
Rapid and accurate diagnosis is critical for starting TB treatment quickly, ensuring good treatment outcomes and preventing TB transmission. There are a few TB diagnostics that are currently available for use globally, as endorsed by WHO.
Some of these technologies are now over a decade old, leading to important diagnostic gaps and limitations to this day. Some molecular tests are available, but they are too expensive to be widely used in many countries. Some tests are cheap, but not very accurate. So, there is no single test that can be used for TB detection satisfying all factors. Launching a new diagnostic that could overcome many obstacles put by the existing solutions would presumably meet the market’s need for more effective and appropriate point-of-care TB tests.
Porter's five forces model
Regulations
When it comes to a new in vitro diagnostic test, all the European Union countries comply with the same regulations established from the EU.
The IVDR (In Vitro Diagnostic Medical Device Regulation) is the new regulatory basis for placing on the market, replacing the EU’s current Directive on in vitro diagnostic medical devices (98/79/EC). As a European regulation, it will be effective immediately in all EU member and EFTA states, without the need to be transferred into the law of respective states. The new rules stipulate more rigorous and comprehensive requirements for CE marking of medical devices in Europe. Manufacturers of currently approved in vitro diagnostic medical devices will have a transition time of five years, up to 26 May 2022, to meet the requirements of the IVDR. Therefore, it is essential for us to comply with the new regulations, in order to put our diagnostic kit on the market.
The most important changes to the current regulations are listed below:
1. General safety and performance requirements are met, including labeling and technical documentation, and quality management systems (Annex I of the MDR and IVDR)
2. New classification, Class A = Low Risk, whereas Class D = High Risk. Class B, C, D need approval by a Notified Body (Annex VIII of the MDR and IVDR). Because our diagnostic kit uses urine as a biological sample which does not contain alive Mycobacterium Tuberculosis bacteria, we consider our kit to belong to Class B of risk classification.
3. More stringent requirements for clinical evidence(Annex XIV of the MDR and IVDR).
4. New requirement: Person responsible for regulatory compliance needed (Article 15 of the MDR and IVDR)
5. UDIThe UDI system provides a consistent and standard way to identify medical devices throughout their distribution and use by health care providers and patients. Most devices will be required to have a UDI on their label and packaging, and for certain devices, on the product itself. ‘Unique Device Identifier’ (‘UDI’) is a series of numbers that enables tracing the manufacturer, device (UDI-DI number) and the unit of device production (UDI-PI number). : Unique Device Identification number for every device
6. EUDAMEDThe European databank on medical devices (Eudamed) is a database that those who manufacture and supply medical devices- such as Notified Bodies, health institutions and Competent Authorities- will have access to. Using this system, those involved in the manufacturing and supplying of medical devices and IVDs will need to register their organization and devices, upload relevant documentation, apply for clinical investigations and performance studies, and upload post-market surveillance documentation. Eudamed is currently being overhauled regarding new regulations to increase capabilities and allow wider access. : European Wide Database for increased transparency and traceability
7. Increased surveillance of Notified Bodies
8. Sufficient financial coverage is in place, in respect of a manufacturer’s potential liability (Article 10 of the MDR and IVDR)
These changes make it even harder for a new diagnostic test like ours to penetrate into the market. Our test needs to meet the MRD or IVDR requirements by carrying out a conformity assessment. After our kit passes the assessment, we will be able to place a CE mark on the product, to show that our kit has met the requirements.
An overview of the procedures that need to be followed in order to place our product on the European Market is shown below:
1. Pass the conformity assessment.
2. Draw up a declaration of conformity ( Annex IV of the IVDR and MDR).
3. Place a CE mark of the device.
4. Assign a basic UDI-DI and provide it to the UDI database.
5. Submit key information about the manufacturer and authorized representative, and importer to EUDAMED.
6. Place our CE marked diagnostic kit anywhere in Europe.
Our Solution
ODYSSEE is aimed to bridge the gap between people suffering from TB and its immediate diagnosis and treatment. We’ve based our research on constructing a new method for early diagnosis of TB not only in Greece, but also in every health facility worldwide.
After the biological sample, urine, is added to our test, a series of reactions begins, including DNA amplification, and transcription/translation, producing an optical result in minimum time. We decided that the result should preferably be a color change, easily observed with a naked eye. Thus, we designed a toehold switch containing the reporter gene β- lactamase. Once expressed, β- lactamase hydrolyzes the substrate nitrocefin which then changes color from yellow to red.
With ODYSSEE, we offer an additional tool to the fight against TB. This affordable test, which can be implemented without the need for specialized personnel, will be used in combination with conventional methods. During the first contact a fast ‘’yes or no’’ result will be available, leading to a more targeted subsequent examination, focused on those who are in real need and to whom treatment will be provided more directly.
Cost analysis
While we were building our prototype, we thought we should contact with our consumables’ (tubes, pipettes etc) suppliers in Greece (Anadrasis MED, 11 Sept 2019) and ask them for the wholesale prices of their product, in order to do an economic estimation. During our interaction, they informed as that they could offer special prices for large orders in the future. This cost refers to the price per test, which is part of the multipack version of our product, leading to a significantly lower price. This version was done because once existing expensive consumables can be used for all test as they don’t come in contact with patients’ sample and, by providing a greater amount of reagents, they reduce the cost of consumables needed for packaging.
Table 1. Total cost per test, considering the cost of each component
In case a device is able to preserve temperature at 42 does not exist, the customer has to supply the alternative version of the test. This version contains a heater device causing an increase of about 10 euros per test. The customer has to buy the heater once as it is reusable. It is worth mentioning that this price concerns the prototype and so it is most likely to be decreased when it comes to mass production.
Customers
We came in touch with different potential customers in our effort to understand whether our test meets their needs, confirming their willingness to use our test in their health infrastructures. We interacted with doctors of the world, WHO Greece, General University Hospital of Larissa, and doctors without Borders who confirmed that our test should be used in Reception and Identification Centres for fast and easy TB screening.
According to the doctors of the World, our test can be useful not only at their facilities in camps, but also at the Open Polyclinics they operate in Greece, helping vulnerable population groups with limited access to health care. They can easily conduct the test in their facilities since there is no need for specialized equipment rather than a fridge and a toilet for reagents and urine sample storage (meeting with E. Thanou and S. Papakonstantinou, 13 May 2019). When it comes to refugee camps, Doctor Veizis from the doctors without borders and A. Sereti from National Public Health Organization (NPHO), suggested that our test should be incorporated in the primary care due to the lack of resources which is covered by our no equipment needed test. Of course, they pointed out that in a case of a positive result, the patient should be transferred to the local hospital for further exams (personal communication A. Veizis 10 May 2019, visit A. Sereti 4 July 2019).
On the 27th of March, we did our project reveal, where doctors from the General University Hospital of Larissa were invited. After our presentation, they were really interested in our test and pointed out that it would be a helpful tool in a doctor’s hands. They didn’t stay at that though; they offered their collaboration by providing us with urine samples in order to perform clinical trials in the future. Considering the competition’s biosafety rules, we agreed to such a collaboration only after the end of the competition (project reveal K. Gourgoulianis and E. Gerogianni 27 March 2019). One of the most important stakeholders, not only for our test, but also for every health tool trying to enter the market, is WHO. We visited WHO Greece, where they were really interested in a triage test that can be used in mass casualty incidents where emergency medical services resources, such as personnel and equipment, are overwhelmed by the number and severity of cases. However, we were advised to come back with a prototype in our hands and then talk about the potential use of our test in European TB programs. For this reason, we are planning to reschedule a visit with our two tubes prototype test for further discussion (visit J. Mikropoulos 9 July 2019)
By interviewing people from Nongovernmental organizations, public, private, but also International stakeholders, we constructed a wide range of diversified costumers with great willingness to purchase and use our test to their health structures.
Business Plan
Thanks to the Ansoff Growth matrix, we were able to understand the risk associated with our growth strategy as well as the opportunities offered. We are providing a new product in an existing market, which means that we are following a product development strategy and our plan should be structured accordingly.
Even if there are a few TB diagnostic tests well established in market, there is no other providing a fast patient screening. We created a low cost and easy to operate POC test which, as it is also indicated by WHO, is a triage test. The health-care providers can use the test during the first contact in order to identify those who need further testing. Afterwards, patients will be transferred to nearby hospitals for further testing using the existing techniques. To better describe our product we performed a SWOT analysis
Funding
As mentioned before, the funds that are given in TB research worldwide are large due to the great need for new innovative tools. Despite the gloomy economic situation in Greece, in 2017, and for the first time in the history of our country, expenses on research and development (not only for TB) were more than 2 billion. This is the right time for a new business step in Greece, considering the fact that the annual GDP growth in the first quarter of 2019 (+ 1.3%) confirms that the recovery of Greek economy continues for the 9th consecutive quarter. In absolute terms, GDP in the first quarter of 2019 (47.94 billion euros) is the highest since the first quarter of 2012 [7].
As the conditions in Greece are suitable, we first thought about the probability of applying for a research scholarship given from the Hellenic thoracic society. Given the fact that the research proposal should mainly concern respiratory diseases and Tuberculosis affects the respiratory system and typically the lungs, we would be able to apply for it. Each scholarship is € 15.000, which will be paid as follows.
Table 2. Detailed description of the amounts paid
During the fundraising process, we came in touch with several government agencies in order to cover the expenses of our project. One of them was the Hellenic Foundation for research and innovation (HFRI). They were really interested in our project and especially in its continuation (personal communication A. Trevlaki 9 May 2019). Considering the great social impact and the needs that such a test could meet, they recommended the program ‘’Science and society’’ which is funded by the Stavros Niarchos Foundation and HFRI. The timeframe for this grant is from 12 to 24 months and the maximum funding for each Research Project is € 250.000.
Timeline
Considering the timeframe that a scholarship gives, we conducted a timeline for 24 months (2 years) with the main actions that have to be taken for our business to grow.
Image 3. Project’s timeline by using the Gantt chart
References
1. WHO (2015), Global Plan Stop to End TB. The Paradigm Shift. August 2016
2. Carniel, E., Shiro, S. K., & Mbassa, V. (2017). Prof. Elisabeth Carniel, Prof. Sinata Koulla Shiro, Mr. Okamura, Dr. Vincent Mbassa.
3. World Health Organization. (2018). Global Tuberculosis Report 2018
4. Diel, R., Vandeputte, J., De Vries, G., Stillo, J., Wanlin, M., & Nienhaus, A. (2014). Costs of tuberculosis disease in the European Union: A systematic analysis and cost calculation. European Respiratory Journal, 43(2), 554–565. https://doi.org/10.1183/09031936.00079413
5. Neglected Disease Research and Development: Reaching New Heights. Retrieved from www.policycuresresearch.org
6. National Documentation Center, [Online] Available from: https://www.ekt.gr/el/news/22334 [Accessed 27th August 2019]
7. Hellenic Democracy, Ministry of Finance, [Online] Available from: https://www.minfin.gr/-/semeioma-gia-to-aep-tou-protou-trimenou-to-2019 [Accessed 27th August 2019]
8. Stevens, P. (2004). Diseases of poverty and the. Public Health. Retrieved from https://www.who.int/intellectualproperty/submissions/InternationalPolicyNetwork.pdf
