Development of tb diagnostics in india a health innovation system perspective

Development of TB Diagnostics in India: A Health Innovation System Perspective Introduction The system building activities for TB diagnostic has evolved and growing in absolute size since the last one decade Even though these are significant development and achievement, but there are issues that restrict the innovating actors to perform at optimal level as desired by the specific diagnostic needs of the country to achieve Sustainable Development Goals (SDGs) in terms of healthcare of country Since the incidence diseases and other health related components are not been addressed through the development of a fully-fledged health innovation system, there is a need to examine the nature and case of various perceived weakness and challenges inherent in the system to meet the purpose of SDGS for providing affordable and accessible healthcare This is important since the level of maturity in MDs innovation system depends largely on the growth of prominent system building actors over the years The present policy and incentive structure for system building activities are found to be largely guided by the commercial and profit making motive of the market in the decision making for MDs development in India The innovation activities of economic actors directed towards meeting the social welfare calculations are even more essential in developing products that cater to both specific health care requirements and cost-effective treatment solutions for lower income quartile populations of the country This is even more significant in the case of technologies that are developed indigenously for specific diagnostic needs and aspirations In order to move away from the market oriented research objectives towards non-market based social calculation of an ecosystem which is responsible for the innovation system of MDs, requires the process of “Valorization” Valorisation is a broader concept than the market commercialization, which is motivated by profit generation mechanism In general, it is a process to create value from knowledge by making it available for economic and societal use by translating them into competitive products, services, processes and new business (Stemerding, 2014) The introduction of this phenomenon could be useful for designing the system building activities in such a manner that it can be useful in the formation of an ecosystem suitable for the development of indigenous technologies Valorisation is a broad concept for ensuring that the outcomes of the scientific knowledge add value beyond the scientific domain It is a “process of realization” of relevant added value products (e.g novel systems or devices derived from genome-based technologies) in a given domain for broad societal benefit This paper provides evidences for such successful case of product development that favored non-market based social calculation to develop ecosystem for the development of indigenous MDs technology and valorizes it, making suitable for local conditions As such, the purpose of the study is to provide a case study of the indigenous MDs technology known as “Truenat” for Tuberculosis (TB) diagnostics developed in India by the young domestic start-up firm “Molbio Diagnostics” The main objective of the study is to analyze the system building activities that are involved in the formation indigenous MDs technology, and to focus on the innovation drivers that have enabled the directions towards local needs The paper is organized in four Sections Section brings out the characteristics and nature of TB and discusses the challenges of building ecosystem for TB control in India The discussion further explores the channels through which new and improved indigenous technologies would address these challenges and issues In Section 3, the study provides the case of the development of “Truenat” and analyses the efficiency of this technology for addressing the country specific TB challenges Section summarizes the study Tuberculosis (TB) Control Innovation Ecosystem in India: Status and Challenges 2.1 Disease Status Tuberculosisor commonly known as TB is an infectious airborne disease It is treatable but according to the World Health Organization (WHO) estimates, the treatment does not reach 41 percent of India’s estimated patients The study done by Steingart, et al (2013) showed that TB kills one person every two minutes in India and 750 people every day India has the world’s highest burden of TB and accounts for nearly one-fifth of new TB cases that occur in the world every year (Chakraborty, et al., 2013) WHO’s global TB report 2012, while concurring this estimates, indicates that India has the largest number of TB patients in the World At the present, the drug resistance of TB is a serious problem compromising both the treatment and control programmes Poor usage of the available anti-TB drugs hassled to progressive drug resistance-multi drug resistance (MDR), extensive drug-resistance (TDR) While drug sensitive TB is curable, MDR-TB is difficult to treat, whereas both XDR and TDR are often fatal Nonavailability of new drugs to treat the drug resistant cases further complicates the problem India witnesses increasing cases of multi drug resistant (MDR) TB , which is currently becoming MDR-TB occurs when TB strains become resistant to isoniazid and rifampicin,which is the most critical first line TB drug increasingly difficult to diagnose and treat A 2015 Global TB report by the WHO estimated the approximately 64,000 cases of MDR-TB emerge annually from the notified cases of pulmonary TB in India In past few years, the WHO has endorsed effective diagnostics for TB such as rapid molecular diagnostics like Xpert MTB/RIF (GeneXpert) and line probe assays These tests are highly accurate with the sensitivity of 88 percent and specificity of 98 percent when compared to culture and smear tests and can detect MDR-TB According to Cochrane (2013), although these tests are available in the public system, but its access to patients is quite limited in India The factors responsible for it are lack of infrastructure, and the expense involved in PCR testing makes it out of reach of most patients In this context, Swaminathan, (2014), states that the “TB control in India requires locally generated tools, solutions and strategies in the areas of There is a need to invest more in research and development and bring together the public and private sectors for effective translation of academic leads into useable products.”Since TB is a huge health problem in India, early detection of the disease with advance technologies, would help in the initiation of therapy and disease management, as well as reduction and spread of TB 2.2 Innovation Challenges Innovation ecosystem for TB control in India is facing various challenges and issues In terms of scientific challenges, the major case is the use of the diagnostic test for TB is identified by the Indian Revised National TB Control Programme (RNTCP) Under RNTCP, the routine TB case is sputum smear microscopy, despite its apparent simplicity and low cost, it requires the experiences and skills to read the slides Moreover, it also has poor sensitivity and unable to diagnose multidrug resistant forms of TB By the time patients identifies sputum smear positive and initiates on therapy, they may have already infected 15 others in their community In contrast to the public sector, the sputum smears are underused in the vast, unregulated private sector that provides care for over half of all TB patients in the country Instead, TB is often diagnosed with inappropriate serological (antibody) test that has long been discouraged by WHO Furthermore, a vast majority of Indian laboratories have virtually no form of accreditation or quality standards According to many researchers and policymakers, innovating new diagnostic tests for TB is therefore one of the greatest challenges for TB control in India Since India has high numbers of TB patients along with a large and unregulated private sector and weak health systems, there is a chance that the potential effect of TB control efforts might eradicate the already achieved success in the field In terms of financial and infrastructure requirement, the capacity of most public laboratories in resource-poor settings is too weak and lack manpower, funds, equipment, and quality controls in a sufficient manner In several cases, the under-diagnosis and poor management of TB creates additional burden and multi-drug resistances Most often, the drug resistance is diagnosed based on clinical symptoms, patient’s history and doctor’s intuition rather than laboratory results Such diagnoses happen only after repeated treatment failures, as the patient does not react to the first line anti-TB drugs For the patient, this means a prolonged illness (including impact on bodily functions, loss of working hours, increasing complexity and toxicity of the treatment), and for the drug resistant TB strains, it provides an opportunity to amplify resistance and spread within communities This suggests that the Indian TB control programme therefore needs new or improved tests for TB control RNTCP is facing the challenge of growing burden of TB, in spite of its huge efforts to expand basic diagnostic and treatment services to cover Indian population Early diagnosis and treatment of patients with MDR-TB is one area where RNTCP needs to improve Currently, most TB patients in the public sector receive only sputum smears as the diagnostic test While most patients eventually get free TB treatment in the public sector, they first seek care at chemists and drug shops and visits informal/unqualified providers All of these result long delays before a proper TB treatment can be started While sputum smears are rapid, inexpensive and helpful to identify the most infectious cases, the current technology lacks required sensitivity and cannot detect MDRTB Therefore, unless patients fail first-line TB drug therapy or have been previously treated for TB, they are generally not being tested for MDR-TB in the public sector clinics In contrast, the private sectors that diagnoses and treats more than half of all TB patients, has been a source of mismanagement of TB and hence drug resistance This includes the use of incorrect diagnostics, incorrect regimens and lack of supervision to ensure all TB patients complete treatment In such a scenario, an ideal treatment is possible only through robust and accurate molecular technologies that could have desired impact on improving diagnosis that are suitable and available that can be used at local resource constraint settings New diagnostic tests for TB that can function in India’s health-care system are urgently needed to alleviate immense human suffering and death In the following section, a case study of indigenously developed diagnostic technology is presented with the characteristics of system building activities that have been undertaken for the formation of the innovation system suitable for specific needs 3 Collaboration of Innovation Actors for Indigenous Technological Development: Case of System Building Activities in the Development of “Truenat” System building activities for the development of Truenat was started with the formation of two innovation system function “Guidance and Direction of Search” and “Entrepreneurial Activity” with a determination of Chandrashekhar B Nair, an Indian based engineer converted into entrepreneur, who focuses on innovations in systems, science, and engineering for the benefit of the society (social innovation) He is the director and CEO of ‘Bigtec Labs’, a product innovation company focused on making gold standard diagnostics affordable and accessible at the point of care in resource- limited healthcare settings He preceded his idea of social innovation under his ‘Frugal Innovation Mission’ for the development of MDs for infectious diseases like TB with the formation of ‘Molbio diagnostics’, a joint venture (JV) company between Bigtec Labs sand Tulip Bigtec focuses on R&D infrastructure to develop indigenous innovative diagnostic tools specifically for countries like India, while, ‘Tulip’, which is a leader in the Indian diagnostics space, has the extensive manufacturing and marketing expertise to cater domestic and International markets Chandrasekhar's idea of the development of MDs for infectious disease prevalent in resource limited settings has been supported with the formation of “Resource Mobilization”, innovation system function, which is evident from the financial assistance of Grand Challenges Canada The association with the Grand Challenges Canada is found to be supportive during all the stages of product developments The major work carried out with the synergy with grand challenge is the development of fully automate sample processing and engineer it to run on a battery-operated portable device Since the major barrier associated with the implementation of MDs at point of care is the sample processing, the development carried under the financial assistance of Grand Challenges Canada would eliminate human error, minimize staff training needs and ensure the MDs could be carried out in the most minimally equipped health Centre Apart from foreign source funding, the development has been significantly supported by the financial assistance of Indian Government through schemes such as New Millennium Indian Technology Leadership Initiative (NMITLI), Biotech Industry Partnership Programme (BIPP), Small Business Innovation Research Initiative (SBIRI) and Technology Development and Demonstration Programme (TDDP) BIPP and SBIRI helped in the providing grants for the validation of test, NIMITLI supported with the grant of soft loan The three innovation system functional aspect has been discussed so far led to the creation of base for the formation of innovation system function called “Knowledge Creation and Development” The study know that the major challenge associated with the development of MDs is to build a knowledge that fill the following diagnostic gaps, namely, (I) Uncertainty in the causative agent leads to misuse of anti-microbial and consequently a build-up of drug resistance, (ii) need of faster and better diagnostics which would lead into automatic reduction in patient suffering and the spread of disease, and (iii) Constraints of high cost and paucity of trained technicians and labs “Molbio” along with the years of assembling multi-disciplinary teams of engineers, chemists and biologists while building a sustained partnerships with prestigious institutions like AIIMS, CMC, IISc, IIT, NIMHANS, NIMR, NIV, SJRI etc., have made it possible to develop a technology called “Truenat” for the detection of high burdened infectious disease like TB “Truenat” is a MEMS-based (Micro Electro Mechanical System based) real-time micro Polymerase Chain Reaction (PCR) device PCR is the gold standard in infectious diseases diagnosis because of its high level of sensitivity and specificity to the disease case However, the traditional PCR equipments are expensive and inaccessible to the marginalized sections of society who are predominantly affected by infectious diseases which requires extensive laboratory infrastructure and skilled operators “Truenat” is a portable and battery operated cost-effective device designed to be used by minimally skilled technicians It also offers rapid detection time of 45-60 minutes To evaluate the performance of “Truenat”a clinical study has been conducted with the Hinduja Hospital Mumbai, result of which is published in a highly recognized International Journal called PLOS One in 2013 According to the published result, “Truenat” has the sensitivity greater than 99 percent in smear positive (S+) and culture positive (C+) cases of TB and a specificity of 100 percent It is able to detect all the TB strainin an evaluation study using a panel from WHO/TDR that contain over 220 geographic diverse strain of TB (Nikam et.al., 2014) Truuenat has following advantage over other MDs called Gene-Xperttest:  Diagnosing TB using Truenat can be about 50 percent cheaper than GeneXpert The technology is chip-based and not cartridge-based like GeneXpert that can be more environment-friendly  Compared with a one ml of sample needed when GeneXpert is used, only about 0.5 ml is required for a test with Truenat MTB  The main advantage of Truenat over GeneXpert is that only when samples are tested positive for TB will tests for rifampicin resistance be carried out This way the use of reagents may be reduced that will help in making the test cheaper  Truenat would be useful for paediatric and extra-pulmonary TB, where the amount of TB bacilli in a sample is low  While GeneXpert is a closed cartridge system, Truenat MTB is an open system — the DNA is first extracted and the testing is carried out using a portion of that DNA If results are not analysed based on one test then one can always retest the sample using the remaining DNA This can be used for any other molecular rmatory test or for testing rifampicin resistance if the test result is positive for TB GeneXpert requires additional sample if the test has to be repeated Drop-outs (patients not returning to provide second sample) can be avoided since Truenat does not need two samples  Truenat would be used to the primary health centre level, which cannot be done using GeneXpert as it needs uninterrupted power supply and air conditioning Knowledge creation and development for the MDs according to the specific needs have fostered the formation of innovation system function, namely “knowledge diffusion” and “Institutionalization and Legitimation” The major issue in the formation and development of such innovation system functions is that the test requires validations once it is ready For instance, “Trunat” has been validated at Hinduja Hospitals The test now needs a drug-manufacturing license issued by the State drugs controller WHO does not have a pre-qualification for TB; however, they endorse tests based on peer review of reported performance In this context, Molbio is working on evaluations by national TB labs towards engaging RNTCP for further adoption At present, the system building activities for the formation of both of these innovation functions are under process and are moving progressively Currently, Truenat is entering in the final leg of performance validation and operational feasibility testing by ICMR (Science Chronicle, 2017) This study is provided with technical assistance and resources by the Foundation for Innovative New Diagnostics (FIND) in order to help commercialising Truenat ICMR plans to take the test to Public Health Centres, which currently use smear samples to test for TB, with a sensitivity level of only 50 percent, which is about half of what the newer method has achieved “Truenat” uses sputum samples for diagnosing TB and is being tested in the field in 100 designated microscopy centres in 50 districts in 10 Indian States The one-month study took place in August, 2017 with nearly 18,000 samples The diagnostic tool has already been installed in 80 percent of designated microscopy centres for testing Validation study carried by ICMR at four sites in India tested nearly 5,000 samples from 2,500 patients The samples were also tested for resistance to the drug rifampicin and the results have been encouraging Besides validating the performance, the focus is on an operational feasibility in field settings The motive of this operational study is to see if the machine performs in hot and humid conditions and whether the machine can work even in the absence of power and lab technicians along with minimum training one can operate the machine All the above innovation systems are functioning collectively to contribute in the creation of “Market Formation” system building activities for innovation system function Since the demand is significant for the MDs “Truenat”, the estimated market size for TB testing varied from 20 million tests per year to over 40 million tests per year (Market and Market’s report, 2016) However, considering the reported number of TB suspect patients presenting to RNTCP, one can say that approximately at least 25 million tests are done per year Therefore, the system building functional actor is adopting market strategies to promote “Truenat” even to the smallest labs and Primary Health Centres (PHCs) all over the country which could otherwise not even dream of doing a PCR test (Nikam et al, 2014) Chandrashekhar Nair in his interview with express pharma, 2016 have said that “we will highlight the anytime, anywhere PCR capability to motivate even field level testing At the same time, we shall be engaging the RNCTP for their adoption of our technology in the programme We plan to take the technology to our 70 distributors worldwide for the deployment in their countries” Thus, the case study shows clearly that once the innovating actors perform on the basis of calculations based on non-market oriented societal goals and challenges, there is ample scope to develop technologies that suit the requirements of wider section of the society It is remarkable to observe that under the severe resource constraint, a young start-up firm is successful in developing a sophisticated but economical MDs technology that effectively diagnosis TB on a larger scale This also point out that such society’s need consideration can result in collaboration of science based, industry based and translational base innovating actors to achieve a common goal and product development Summary The “Truenat” case study presented in the paper shows clearly that the problem solving approach directed towards system-building activities have made it possible for the development of indigenous technology The System building activities that is guided by the non-market based social calculations have favoured the valorisation of the technology for the development of social innovation Interaction between different actors is the significant characteristics of ecosystem developed, that has provided the strength for the formation of system building activities for each innovation system functions Conducts and performances of innovation actors for building up of innovation system functions found to be specifically oriented towards the local needs Since the study have seen the critical role of government in shaping various innovative functions, it is being observed in this Case study that, there was continuous support from the government that has provided strength to the system building activities The special feature of the ecosystem for innovation, developed for this technology is the orientation of entrepreneurial activity for social innovation and initiative undertaken for frugal innovation by the innovator firm Continuous interactions with various prestigious institutes of science base have helped in overcoming the challenges and strengthened the knowledge creation for indigenous innovation Since technology in biomedical, the system building activities for translational research i.e., its clinical evaluation and validation, have been significantly supported by the Hinduja hospital and Indian Council of Medical Research (ICMR) to confirm clinical effectiveness of the technology This case study confirms that if the system building activities for innovation are guided by the problem of solving non-market based social calculations then it would help in building an ecosystem for the development of indigenous technology required for addressing the country specific needs and challenges  ... challenges for TB control in India Since India has high numbers of TB patients along with a large and unregulated private sector and weak health systems, there is a chance that the potential... reduction and spread of TB 2.2 Innovation Challenges Innovation ecosystem for TB control in India is facing various challenges and issues In terms of scientific challenges, the major case is the use of. .. is able to detect all the TB strainin an evaluation study using a panel from WHO/TDR that contain over 220 geographic diverse strain of TB (Nikam et.al., 2014) Truuenat has following advantage