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Standard Template for a Candidate Demonstration Project

1. *Title of the Project

Combating Tuberculosis in the Region by development of Diagnostics and Drugs

This can be achieved by the following:

A. Diagnostics:

Combating Tuberculosis in the region by deploying a sensitive, indigenously developed, novel molecular platform for detection of Mycobacterium tuberculosis (MTB) and simultaneously detection of the subset of Rifampicin (Rif) drug resistant patients at the Point of Care (PoC) setting.

The developed tool to be validated against the existing gold standard (liquid culture) and head to head comparison against the WHO endorsed technology platform for regulatory approvals in South East Asia Region (SEAR) countries for point of care use.

B. Drugs:

Developing a translational platform for clinical development of TB drugs through demonstration project of novel regimens for the treatment of MDR-TB - Phase IIb trial of the novel combination PA-824 + Moxifloxacin + Pyrazinamide.

2. *Submitted by

A. Diagnostics: Translational Health Science and Technology Institute (THSTI); Biotechnology Industry Research Advisory Council (BIRAC), India.

B. Drug: Open Source Drug Discovery (OSDD) programme of the Council of Scientific & Industrial Research (CSIR), India

3.*Target Disease or health condition

Tuberculosis (TB) is a communicable, airborne infection by Mycobacterium tuberculosisand occurs typically when a person inhales microscopic droplet nuclei containing viable bacteria, spread through coughing by persons who have infectious TB. The disease has become a major public health problem as undiagnosed, untreated person with active pulmonary TB disease can infect other people. On average, only 5-10% of those infected with MTB will eventually develop active disease.One-third of the world's population get infected with M. tuberculosis, and new infections occur at a rate of one per second approximately. It ranks second most common cause in terms of death by infectious disease after HIV. Depending upon the incidence, TB has been categorized as Type II disease by WHO. Additionally, Multi drug-resistant TB (MDR TB), extensively drug-resistant TB (XDR TB) and HIV infection, poses excessive public health challenges.1,2, 3

4. *The suggested health technology that project seeks to develop

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A. Diagnostics:

An affordable and high quality point of Care (PoC) diagnostic test for TB, the product of Research and Development (R & D) innovation, developmental processes in India. A rapid TB diagnosis facilitate a patient to sooner initiation of treatment to mitigate the debilitating symptoms of the disease and also restrict the potential for transmission.4A molecular test, more sensitive than microscopy, can be developed to get more people on TB therapy and reduce delays5.

Currently, there is no PoC diagnostic test available in the South East Regional countries which can tests for TB detection as well as Drug resistance cases at the same time. Early diagnosis has its importance to bring down the incidence rate 1.Several products are under development, but newer Nucleic Acid Amplification (NAAT) based tests, which are close to market are need to be rapidly evaluated for rapid integration to the system as well as to generate evidence for policy review.

There are constant efforts in R & D for successful development of new product or refinement of the existing diagnostic tests in India. Some of the following promising pipeline diagnostics which are in the advanced stages of development have been described as follows:

Table: R & D Matrix for potential target platforms for diagnostics from India (6, 7, 8, 9)

The more detailed current mapping of the promising diagnostics in the Regional countries will also be performed.

Name of Company

Selection Criteria

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Based on the above comparison, the Molecular platform, developed in the private sector with support from Government R&D programs like New Millennium Indian Technology Initiative (NMITLI), Biotechnology Industry Partnership Program (BIPP) and Indian Council of Medical Research (ICMR)’s extramural grants is a collaborative project between public private partnership will be modified for the simultaneous detection of TB and the drug resistance in patient which will be truly innovative.

The platform is currently commercially available for diagnosis of MTB in sputum and at present does not have a provision for Rif.resistance testing. The developers are in the process of refining the platform to include rifampicin resistance testing. The key refinements that is required for this platform to be a point of care test is to automate sample preparation and include the rifampicin detection protocol as a follow-on procedure in order for the test to be user friendly and improve access and early diagnosis of TB in high burden setting where the peripheral health care settings require a simple low touch technology platform for it to be rapidly integrated for testing of TB and drug resistance which can be scaled as a credible alternative to existing automated molecular testing platform.

B.Drug:

The project seeks to develop a translational platform for clinical development of TB drugs in multiple centres through a demonstration project involving a novel regimen for the treatment of MDR TB. The novel regimen has completed Phase I and Phase IIa studies in South Africa under the aegis of the Global Alliance for TB. The concept of developing and bringing novel regimens for the treatment of MDR TB is changes the paradigm of drug development and at the same time prevents the introduction of one ‘new drug’ at a time into a failing regimen, which is the cause of the ‘induction’ of drug resistance.

5. *Project Summary

A. Diagnostics:

One-third of the world's population get infected with M. tuberculosis, and new infections occur at a rate of one per second approximately. It ranks second most common cause in term of death by infectious disease after HIV3. MTB is an airborne pathogen causing the TB disease by the droplet particles released to air when pulmonary TB patient coughs. Globally, especially in the entire six WHO region, the incidence rate of new TB cases has been falling over the last decade, achieving the MDG global target. However, the rate of decline of 2% per year needs to be leveraged to achieve the Stop TB elimination target10. TB deaths each year, are partly due to late or missed diagnosis, hence, improving the performance (sensitivity and Specificity) of diagnostics and their availability are key to reduce global and regional morbidity and mortality. The delay in diseases detection is directly related to lack of availability of PoC diagnostics and drug resistance TB detection tool. The majority of the TB (60%) is detected at the peripheral health care setting emphasizing the need for PoC test11.

In South East Asian regional countries, sputum smear microscopy is the most widely used diagnostic test; however it has low sensitivity and misses almost half of the pulmonary TB

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cases. Culture, which is the gold standard for drug sensitivity testingis not easily accessible as a tool for basic screening and diagnosis of DR TB cases. Hence, there is a real need for development and deployment of a Point of Care tests for TB, which can really be used at the peripheralhealth care systemfor testing the detection of MTB at PoC level and inclusion of drug resistance in the same sputum sample.

TB treatment initiation by the current drug regime need prolonged treatment by toxic drugs, thereby open the scope of non-compliance. Moreover, resistance arising to the major drugs to the first line of defence adds up the complexity. The only available BCG vaccine has several limitations and need replacement and modification. TB cannot be treated presumptively; a definitive diagnosis must be made before treatment initiation12. Importantly, to address the unmet need of WHO Stop TB program and the Millennium Development Goal 6, an appropriate Point of Care diagnostic, which is currently unavailable, is needed for the countries in the South East Asia region which has huge burden of TB disease of all types (MTB, MDR, XDR).

The diagnostics for TB ranges from the conventional microscopy of sputum samples to new age Phage detection system, serodiagnostics, Nucleic Acid Amplification tests, Immunodiagnostics, Interferon Gamma Release Assay (IGRA), T spot TB test, Loop Mediated Isothermal Assay (LAMP) etc. The recently developed real time PCR based GeneXpert MTB test by Cepheid, USA has been evaluated in field conditions in India and the TB control programme is adapting this in large scale. However, the cost and the need for constant power supply have restricted its use as a truly PoC test for TB in India. Importantly, WHO’s negative policy on TB serodiagnostics, has discouraged the use of commercial serological tests for Tuberculosis, India has banned the use of these tests for TB diagnosis. There is advocacy for a robust, reliable, rapid, sputum based NAAT/ molecular test which has better sensitivity than smear microscopy and shows accuracy like Xpert MTB/Rif providing same day result and can be deployed at the peripheral microscopy centers in the SEA regional countries5.

Objectives:

To support and refine an indigenously developed chip based nucleic acid amplification technology for a point of care test to detect TB and to detect rifampicin resistance as a follow-on process, with the same elute from the earlier prepared sample

On confirmation of “proof of principle” to further support validation, demonstration studies for use under programme conditions as a PoC in the health system for rapid diagnosis of TB and rifampicin resistance.

The test will be registered for use through the Drug Controller General India, (the Indian FDA counterpart) the regulatory authority for detection of TB. The test can potentially be deployed for validation for early diagnosis of MTB in the public sector. Validation through Indian centres of excellence in TB research like National Institute of Research in Tuberculosis, Chennai (NIRT), National Institute of Tuberculosis and Respiratory Diseases, New Delhi (NITRD), JALMA Institute of Leprosy and other Microbial agents, Agra (JALMA) etc. would create a body of data for the national programs consideration.

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The refinement for inclusion of rifampicin resistance detection is absolutely essential keeping in mind the prevalence of drug resistance in countries like India which accounts more than 80% of MDR TB in the SEA Region. At the global level Foundation of Innovative and New Diagnostics (FIND) will be contacted for multi-country studies in parallel.

THSTI in coordination with ICMR could coordinate in county studies as detailed above. In addition, THSTI could leverage its resources to help improve the platform for development/validation of resistance, improvement in sample preparation and automation of sample to result platform to keep it constantly relevant.

Funding could be leveraged for the above development Cartridge/chip based NAAT are promising for accuracy and speed of diagnosis due to the inherent technology safeguards, which prevent cross contamination and hence false positivity during the testing procedure. This project is looking for options for easy to use test refinement/ modification of the existing promising indigenous product targeted as PoC. This is a chip-based PCR test in the detection of MTB in clinical sputum specimens, run on a battery-operated, automated microPCR device with semi-automated sample processing which has shown sensitivity and specificity of more than 95% respectively 6. The preliminary study shows that the test allows detection of TB in approximately one hour.

However, the platform would benefit for increasing the ease of useat the Point of Care setting, such as:

a. Total automation of specimen processing b. Inclusion of drug resistance platform c. Creation of a sample to result system d. Automated sample prep version and the integrated version need to undergo

evaluation studies. e. It is proposed that development and validation of this platform through the large

evaluation study in India which can be extended to multicountry validation studies in other countries of SEAR would be done before the product can be deployed widely as a diagnostic test for TB at the peripheral level.

f. Inclusion of drug resistance platform in this and validation will help to introduce it at the referral level too. Hence, both the health care level will be taken care off.

The recent “Global Tuberculosis report, by WHO, 2013 has mentioned the possible approaches including the micro-PCR based system made in India as one of the promising lead candidate ,however has limited evaluation data from the country set up. The most important aspect for a product development is timely investment of finances to support the R&D for refinement and automation. Hence this project could be the path breaking innovative initiative for the development and use of a product that could be a cost effective, low touch PoC especially useful in high burden resource constrained countries like India, Indonesia etc.

B. Drugs:

Background: The medical need:

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The need of new drugs for TB is recognized by experts around the world. Development of new drugs for TB has special relevance to the South Asia as the WHO SEA Region bears about 40% of the global burden of TB. The initiatives by the product development partnerships (PDP) like Global Alliance on Tuberculosis (TB Alliance), pharmaceutical companies like Janssen Pharmaceuticals, Otsuka Pharmaceuticals, Astra Zeneca, Pfizer, etc, have brought a pipeline TB drugs to the development phase of clinical trials. In December 2012, the U.S. Food and Drug Administration (FDA) approved Janssen’s drug Sirturo (bedaquiline) as part of combination therapy to treat adults with MDR TB when other alternatives are not available, in the United States. While the drug pipeline looks promising, very few institutions in SEA region have the capacity to participate in the drug development efforts, particularly clinical trials. In this situation, the drugs are getting developed in advanced markets and approved by agencies like FDA, while SEA region is lagging behind, limiting access to and causing delays for efficacious drugs to reach the deserving patients.

The proposal is to set up a drug development platform for TB in the countries with disease burden in collaboration with competent institutions in public and private sector in such countries. The most expensive and risky part of drug development process is conduct of clinical trials. Once such a platform is established the PDP organisations, public funded efforts and pharmaceutical companies working on discovering and developing drugs for TB will be able to conduct development studies of drugs in these countries. This is expected to make drugs available to the patients without much delay of its launch in advanced markets, making these drugs accessible to patients in need and affordable as the cost of development will be comparatively less in the developing world. This proposal is expected to derisk the drug development process to a large extent, improve the speed of introduction of the drugs into disease burden countries with the promise of affordability and accessibility. The above approach is demonstrated through the proposed novel MDR regimen trial of OSDD of CSIR, funded by the Government of India. The CSIR-OSDD programme has been able to put in place the necessary ingredients for clinical development as demonstrated below and this is a replicable model scalable to conduct clinical trials of a number of TB drugs in different countries.

The Concept:

MDR-TB treatment requires 24 months of a regimen that includes a Quinolone and an injectable along with 4 other drugs. The treatment is toxic and cumbersome leading to poor compliance and limited success. A novel well-defined single regimen with efficacious drugs that can shorten the duration of therapy is a dire and urgent requirement.

The treatment of Tuberculosis faces a new cliff, a cliff with several novel drugs in late stage clinical trials but with the danger of them being introduced one at a time into a failing regimen which would indeed be a rapid death knoll for the new drug. The need of the day is the development of novel regimens, which can be used for the treatment of drug sensitive (DS) and MDR TB. The current treatment of MDR-TB is a 24 month regimen consisting of Moxifloxacin + Levofloaxacin + Pyrazinamide + injectable Aminoglycoside + Cycloserine + Ehtionamide +/- Clofazamine.

The TB Alliance (a not for profit PDP) pioneered the concept of progressing novel regimens for TB through the development of a combination of PA-824+ Moxifloxacin + Pyrazinamide

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(PaMZ). This combination includes PA-824 which is a novel ‘nitro imidazopyran’ that has completed extensive Phase I and Phase IIa trials on DS TB patients in South Africa and found to be efficacious and safe (multiple 14 day studies) in humans. Moxifloxacin and Pyrazinamide are currently in use for the treatment of MDR-TB.

The project approach and design:

The current design of the Phase IIb clinical trial entitled “A Phase II Open Label Randomised Clinical Trial to evaluate the anti bacterial activity, safety and tolerability of a combination of PA-824, moxifloxacin and pyrazinamide, or PA-824 when administered with the Category IV regimen of RNTCP in adults with newly diagnosed multi-drug resistant pulmonary TB.An 8-week study intends to evaluate the efficacy of the regimen on MDR patients along with studying the safety of the regimen over this period. This will be first major study of the regimen on MDR patients as most of the previous clinical studies with the regimen have been on DS patients.

The project design also includes the study of:

1. The pharmacokinetics of the drugs at various intervals of treatment to determine the exposure and metabolism in Indian patients. 2. Pharmacogenomic study: it is envisaged to sequence the genome of all the isolates, as well as determine the genomic status of the patients in terms of the known transporters and metabolizing enzymes. 3. It is envisaged to concomitantly study the ‘bacterial load’ as a prognostic marker using the newly developed diagnostic kits, Truescript byBigTec and that developed by Reametrix.

Current status of the clinical trial:

The study protocol has been finalized, applications seeking permission in the prescribed format submitted for clearance with the Drug Controller General of India (DCGI) and the final clearance is awaited.

Partnerships:

CSIR-OSDD has licensed the novel combination for developing, producing and marketing the product for India from TB Alliance.

The investigator hospital is NITRD, a public funded hospital under Ministry of Health.

The protocol and Trial designs were finalized by NIRT, Chennai, a research hospital under the ICMR.

CSIR-OSDD is the sponsor of the trials. OSDD has approached the Government of India for funds for the Phase IIb trial.

OSDD is also investing in one location to develop competence in conducting clinical trial. This location is a publicly funded hospital where infrastructure and competence is available,

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which needed to be fine tuned and topped up to meet the challenges of conducting clinical trials of internationally acceptable standards. This additional requirement is brought in by OSDD.

OSDD treats the drug development as a pre-competitive activity. OSDD is not expecting return on investment and will not charge any royalty from the manufacturers and will license the drug non-exclusively to facilitate generic manufacture and competition in the market place which will make the drugs affordable and accessible. The drug developed by OSDD will be available without royalty to the developing world. The reason for not charging royalty is multifold. It reduces ultimate cost of the drug. It also factors in the fact that public funds have already been used for development of the drugs. In most developing countries TB drugs are administered through government agencies who are the purchaser of the drugs. Charging royalty on the drugs developed out of public funds which will be purchased by public exchequer will only be meaningless.

OSDD brought together a wide ranging group of expertise to conduct the proposed trials. The entire effort treats the drug development phase as a precompetitive collaborative phase. Once developed, the drug will be licensed to manufacture by generic manufacturers. This is a scalable and replicable model and any organization with the required competence can replace OSDD. If multiple facilities can be created and manpower trained for conduct of clinical trials, any new drug being brought to market can use this platform.

6.*Public Health need that the proposed project aims to address

A. Diagnostics:

Burden of Disease- TB is a highly prevalent infectious disease, acts as a major global health threat which disproportionately affects low & middle income countries which accounts for 95% of 12 million cases globally. An estimated 8.6 million people developed TB and 1.3 million died from the disease as per the global data in 20121.Geographically, about 60% of cases are in the South-East Asia and Western Pacific regions with the majority of cases in 2012 were in the South-East Asia (29%).The current disease scenario in the regional countries has been depicted that all the member countries have high TB cases, high MDR-TB cases and high HIV-TB cases. India, China, the Russian Federation and South Africa have almost 60% of the world’s cases of MDR-TB. WHO SE region with WHO 11 member States depict the prevalence number as 4800 (In Thousands) and Incidence number as 3400 in thousands.The major reason for this burden is the delay in diseases diagnosis and the absence of any PoC test to detect the disease and the drug resistance simultaneously using the same specimen. Hence, a new proposal on development of an effective diagnostic for improved case detection and newer drug regimen for addressing TB problem in the South East Asia regional countries is being submitted.

The current drug regime involves 6-8 months of prolonged treatment and non-compliance by patient lead to emergence of drug resistance cases. The existing diagnostics such as sputum smear microscopy has several shortcomings including low sensitivity.

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Since diagnostics development involves less regulatory concern, cost effective, less time consuming than drug & vaccine development, short term project fora TB diagnostic is proposedwhich may have greater return of investment.

The novel diagnostic technology is based on real time PCR by a battery operated simple yet robust machine, the test can be performed outside of laboratories and hospitals by non-laboratory technicians. This has shown sensitivity and specificity of high range, user friendly and will be affordable fulfilling the ASSURED criteria12,13(Annexure I). However, to bring the appropriate product for the mass, huge financial support is warranted.

Strengths in the SEA Region

India, Indonesia, Thailand have capacities in pockets to support the validation of this technology. The details are placed in Point No. 11. In addition, India has several Centers of Excellence and the capacity of both R & D and manufacturing ability involving Research Institutes & Universities like NIRT, JALMA,International Center for Genetic Engineering and Biotechnology (ICGEB) , Delhi University, South Campus, New Delhi (DUSC) All India Institute of Medical Sciences (AIIMS), New Delhi. Government Funding Agencies have funded many TB basic and immunological research; human Resources in the form of highly trained manpower for R & D and the diagnostics Companies and Manufacturing Infrastructure.

A recent study estimated that about 40 Million tests are conducted in India for diagnosis of TB both in the public and private sector. However, the case detection and time required from the first contact with healthcare centre to final diagnosis of TB leaves a lot to be desired. A NAT test which is comparable in sensitivity to culture would significantly enhance case detection.

B. Drug:

The project proposes to put in place a translational platform for neglected diseases as a precompetitive collaborative space which can be used by industry or other research organization to develop drugs for neglected diseases. The above approach is demonstrated through the conduct of the proposed trial of a novel combination for TB.

India is one of the capitals of MDR TB patients, major improvement in the diagnosis and treatment of this affliction is indeed a national priority. The project addresses these issues by:

a. The current treatment of MDR TB is a treatment empirically arrived at with most of the drugs in the regimen having been previously used and discarded because of their toxic side-effects as well as poor efficacy. Thus the current ‘standard of care (SOC)’ of a 24 month treatment duration with the combination of ‘a quinolone, injectable aminoglycoside, Pyrazinamide, Ethionamide and Cycloserine. Several permutation combinations with other agents like clofazamine or PAS are also used depending on the response and the ability of the patient to tolerate these drugs. The success rates are far from satisfactory bordering around 50 to 75% and can be as low as 30% in certain regions. The major challenge with SOC is the management of side-effects which reflects in poor compliance and further complications. Another added factor is the lack of standard defined prescriptions that lead to use of combinations, which potentially can destroy the ‘limited efficacy’ of these second line drugs.

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What this projects aims to change:

• Develop a standardized 3 drug regimen that is both more efficacious and safe. • Shorten the duration of therapy. • Eventually aim for a single regimen for both DS and MDR TB. The current phase of the development programme is critical for the advancement of the combination through the subsequent phases. b. The project will allow the building of both expertise and infrastructure for carrying out TB drug trials in India that can enable the testing and development of novel anti-TB regimens. This is a critical requirement for the country. It will also encourage building a ‘translational platform’ for meaningful clinical research towards the development of novel regimens.

• The translational platform for the planned Phase IIb study currently envisages inclusion of:

o Testing viable diagnostic kits as prognostic tools. o Develops pharmacogenomics applications to treatment of TB. o Builds a repository of clinical isolates and samples collected during this study.

The project is planned to be carried out at the NITRD, Delhi which has the necessary infrastructure to hospitalize MDR TB patients which is a requirement for this study. The project will allow the building of necessary expertise as well incorporate newer technologies o Line Probe Assay (LPA) for second line agents, o Time to positivity concepts using MGIT and comparison with standard colony count determinations. o Build necessary protocols and procedures to work with clinical Contract Research Organisations (CRO) for conducting Phase II clinical trials at global standards.

Another major goal of the programme is to develop multiple clinical sites along the lines that is being currently planned at NITRD. This will expand the capability as well shorten the duration of the trial. Clinical Development Services Agency (CDSA) a unit affiliated to the THSTIof Department of Biotechnology (DBT), Government of India will be a partner in creating and setting up such multiple facilities. Availability of these clinical research platforms through this programme will have a major impact on our ability to address this public need.

7.*Explain which New & innovative approaches and mechanisms to supporting financing and coordination of R & D this project would demonstrate?

A. Diagnostics: Involvement of inter country Government Department and Council along with WHO as the major facilitator, will boost the Industries to venture together for the development of the diagnostic device on large scale.

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The proposed project has a promising lead as a need for novel diagnostics development and/or delivery to be catered for the most dreaded disease for the poor which needs immediate action. The technology will be fulfilling the ASSURED criteria existing for the diagnostics and will be better than the existing ones. This will be supported by pooled funding.

Some of the following coordination of R&D would be demonstrated as: Consortium: Creation of a consortium of like-minded partners including developers, Foundation of Innovative Diagnostics (FIND), UNITAID, StopTB partnership, WHO and Ministry of Health (MoH) from partnering countries from the very beginning. Open access repositories: can be made in different partner regional countries which will include validated sera panel and the diagnostic and drug candidate can be validated in the respective set up which will be real value addition.

Computational resources: Will be initiated in the regional partner countries

Open Screening facilities: will be initiated in the regional partner countries for drug screening.

Inter-country Governmental Pooled funding : the partnering countries will be negotiated and brought together for pooled funding of their R& D finding resources to strengthen the work development.

The financing mechanism for health research and development will be a novel approach like:

Product Development Partnerships: the public players such as Department of Biotechnology (DBT), Indian Council of Medical Research(ICMR) and Ministry of Health could be partnered with the facilitatory support by WHO, with Bill and Melinda Gate Foundation (BMGF), FIND, the Program for Appropriate Technology in Health (PATH), The Infectious Diseases Research Institute and US National Institute of Health consortia for point of Care diagnostics development of the product at the various stages of the product development pipeline. The donors work with diagnostic companies to develop PoC diagnostic tests for TB. The Grand Challenges Canada by Canadian Government has initiated provide support for call for proposals for the POC test development. WHO can facilitate in leveraging funds from several conventional and unconventional donors and country governments for supporting the development of the diagnostics. Delinking the cost of R&D from the product price: De-linkage of the R&D cost from the product price will eliminate monopolies on final products which will permit a much more decentralized system of manufacturing, distributing and marketing. In the proposed project, the de-linkage component will already be in-built.

Prizes to incentivize and reward diverse diagnostics and drug discovery efforts which will promote open sharing of innovations from the researchers with others and license the relevant IP to a patent pool. The milestone prizes can be introduced for rapid development of the technology.

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Grants to support clinical trial: Public financing need to be made available to push the promising compounds through clinical trials.

B. Drug:

The challenge in neglected diseases is to overcome the market failure by creating a translational platform that will enable any entity that develops drugs to conduct the risky clinical trials, especially in the context of neglected diseases in a resource limiting environments. This can be achieved through multiple mechanisms of support through public funds, philanthropic funds, optimal use of existing investments in research whether in laboratories or in hospitals, product development partnerships, enabling private sector participation, and creating an enabling environment for the PDP, public funded organisations, pharmaceutical companies and other relevant drug discovery teams to develop drugs in the countries where the disease is prevalent.

This proposal envisages creation of core facilities in hospitals in developing countries to conduct clinical trials and to train personnel for conducting such trials. This core investment will set up a platform that will enable pharmaceutical companies and the other entities who develop drugs to carry out trials.

The project proposes to put in place a translational platform for neglected diseases as a precompetitive collaborative space which can be used by industry or other research organization to develop drugs for neglected diseases. Such a platform does not exist anywhere else. Funding the establishment of the platform through public funds de-risks the costly clinical development of drugs for TB and other diseases to a large extent. The platform is scalable in TB and replicable in other neglected diseases.

8. *Evidence of Market failure/research landscape A. Diagnostics:

The high mortality rate due to TB in the regional countries suggests the non-availability of user friendly, affordable technologies at primary care facilities as because, this kind of test requires huge R & D effort followed by validation to be useful for the particular Geographical area.

The prototype technology was supported by novel investment strategies between public- private funding in India and has a promising lead. However, to bring forward the technology to the people, more investment is needed for refinement in R & D, validation, up scaling and introduction in the market. The partnership is planned for validation of the test in the countries using the clinical specimens and establishes their utility and performance in this particular region. Due to the absence of suitable tests and drug the approach is novel focussing the regional countries and will be more efficacious and has less risk formarket failure. Hence, an innovative method of financing involving Indian and multicountry Government funding agencies and WHO is proposed.

While investment into development and deployment of such diagnostic tests are a major cause of failure of such tests being available, the other major path is the unclear requirements for an indigenous test to be available in the national program. For a disease

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like TB, only the national program could provide the volumes needed for commercial success of any platform. A clear path towards adoption of technologies needs to be piloted and THSTI is ideally poised to do this.

B. Drug:

R &D in neglected diseases is lagging because of market failure. Due to the lack of market incentives, the complex nature of disease and treatment which is often a combination therapy and the regulatory environment surrounding them making access to the market a complicated exercise. Due to this complex environment research based pharmaceutical enterprises do not have incentives to invest in neglected diseases.

Patents are regarded as one of the most important incentives to invest in pharmaceutical R&D, allowing recouping of huge expenditure involved in biomedical R&D. Patents incentivise private sector to develop and market products to address health needs where commercial prospects exist. However, where markets have limited purchasing power, not substantive enough to ensure the return on investment, the incentives disappear removing private sector interests in R&D. Patents or other measures ensuring exclusivity in the market loses its relevance due to this market failure. This is the case of tropical infectious diseases affecting millions of poor people in developing countries, thereby these diseases being called, ‘neglected diseases’. An example of such market failure is tuberculosis (TB), where global market is estimated to be about US$ 300-400 million, while cost of drug discovery is estimated to be US$ 800 million upwards. Hence, there is a basic economic case for public investments to develop diagnostics, vaccines and medicines that are needed for diseases of the developing countries.

The pipeline of TB drugs that has come into existence is not being developed in the South Asian region which harbours 40% of the disease burden. The pharmaceutical companies could not be blamed for this as infrastructure to develop such drugs does not exist in many of these countries. Even in India which has drug manufacturing capability, there are very limited facilities to conduct clinical trials in complex diseases like TB which require appropriate bio safety level containment facilities even in hospitals.

The requirement is to set up a string of clinical research facilities in the countries where the disease is prevalent, to enable pharmaceutical companies and other entities to do clinical trials.

In addition to setting up of infrastructure, the personnel manning these facilities have to be appropriately trained to equip them to face the challenges in conducting clinical trials at internationally acceptable standards. In the current proposal such training will be imparted through experts with international experience in the field. It is also proposed to expose the investigators to some international facilities conducting such trials so that they can learn from such experiences.

OSDD has initiated the process of developing such a platform in one such location, NITRD based at Delhi. The proposal here is to develop such multiple platforms in different locations and train the personnel to enable them to conduct clinical trials. This will enable conduct of clinical trials of a number of anti-TB drugs in disease endemic locations.

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9. The scientific and technical feasibility A. Diagnostics:

The objectives of the project are scientifically and technically feasible as the partners have all relevant expertise, know–how and well proven track record to perform the required tasks.The researchers have already initiated the development of several molecular platform technologies,microchips etc.The National Institutes havealready developed various molecular primers for PCR based diagnosis. The country has demonstrated expertise in development of chip based cartridge with various self-contained attributes and the validation could be easily performed within public/ private organization.Importantly, the Government has a requirement for a point of care TB diagnostic device, and due to huge market demand, the interested partners and developers will venture in the manufacturing of the developed device.

Scientific and technical background: The proposed platform does real-time PCR by performing rapid thermal cycling on a chip. Real-time detection happens by monitoring fluorescence using a novel low cost optical system. Mobile phone technologyfor data transmission centrally is inbuilt in the platform. Battery operation enables deployment in settings where no electricity is available. No additional infrastructure other than what is packaged and supplied by the company is needed to run the test. Sputum samples are processed using magnetic nanoparticle based extraction using a battery operated device. The entire system can easily be used by minimally trained healthcare workers with one day training.

Methodology:

a. The independent PCR capable of running one sample at a time was developed first along with the menu-driven sample processing system. This only requires pipetting skills

b. Sample prep is being fully automated to be a walk away system c. A four chip PCR system with random access will be available shortly d. The developer will work on a sample to result, “hands-free” platform integrating

sample prep and PCR.

The battery-operated platforms for both sample preparation and PCR has been developed. Also, a sputum processing kit has been developed for use on its sample preparation device that a chip-based PCR test for molecular diagnosis of MTB. The developer will leverage the experience and expertise inculcated in the development of these technologies to bringing out the proposed platform. It has proof-of-concept data for the automated version of the sample preparation and for low cost plastic chip-based PCR. Integration of the sample preparation and PCR is the only risk, which can be mitigated by using an academic/industry partner with expertise in that domain.

At each stage, the products from development are commercially deployable as a complete package, with constantly enhanced ease of use.

B. Drug:

There are a number of organisations around the world who are working on neglected diseases and has progressed their work considerably on the drug discovery phase. They

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need a translational platform to take the drug through the development phase. The OSDD demonstration project shows that it is scientifically and technologically feasible to put in place such a platform as a precompetitive collaborative effort with public funding. Once developed the platform is available for anyone to develop a new drug.

Background:

TB Alliance has progressed a novel combination of PaMZ through Phase I and Phase IIa clinical trials on DS TB patients with an intention of developing this therapy for the shortening of therapy for both DS and MDR TB patients. The Early Bactericidal Assay trial for 14 days was conducted in South Africa14 where the new combination was shown to significantly efficacious and better that the Rifafour regimen currently used as first line therapy. The regimen has completed a Phase IIb, 8 week clinical trial in South Africa on DS TB patients and a few MDR TB patients. The results are expected shortly but preliminary analysis ( personal communication) indicates that the regimen is not only safe but has the potential to reduce the duration of therapy. However this trial has too few MDR TB patients in the study.

CSIR-OSDD has licensed this combination for development, manufacturing and marketing in India and plans to progress the same under the OSDD principles defined under points 8 and 14 of this document.

Scientific and Technical design:The partners for this programme are:

1. CSIR-OSDD being the sponsor of the project

2. Dr. Rohit Sarin and team from the NITRD New Delhi.

3. GVK-BIO as the Clinical CRO providing the support and documentation services.

The trial is envisaged to be carried out at the LRS hospital, New Delhi which is a accredited organization for the treatment for MDR TB under the DOTS Plus programme and has the necessary infrastructure to isolate and hospitalize MDR TB patients after screening through the prescribed formats.

Design of the trial: The trial consists of 3 arms each of ~100 MDR MALE PULMONARY TB patients recruited based on well defined inclusion and exclusion criteria defined in the protocol (attached Annexure 1). The 3 arms being:

• Regimen of PaMZ. • Regimen of Pa823 + SOC ( Moxifloxacin, Pyrazinamide, Amikacin, Cycloserine and Ethionamide) • Regimen SOC only. The patients will be enrolled based on detailed Line Probe assay testing for both first line and second line drugs as well as testing with standard Drug Sensitivity Testing (DST) for the same. The main objectives of the trial as described in the ‘protocol document are:

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Primary Objectives: To evaluate the antibacterial activity of a) A combination of PA-824, moxifloxacin and PZA, and b) PA-824, when added to the Category IV regimen of RNTCP when given for 8 weeks in patients with newly diagnosed pulmonary MDRTB. Secondary Objectives: a) To evaluate the safety and tolerability of i) a combination of PA-824, moxifloxacin and PZA, and ii) PA-824 when added to the Category IV regimen of RNTCP, when given for 8 weeks in patients with newly diagnosed pulmonary MDRTB. b) To study the pharmacokinetics of: i) PA-824 when co-administered with moxifloxacin and PZA, ii) Moxifloxacin and PZA when co-administered with PA-824, iii) PA-824 when co-administered with the drugs of Category IV regimen of RNTCP (injection kanamycin, levofloxacin, ETH, EMB, cycloserine and PZA), iv) Drugs in the Category IV regimen of RNTCP when co-administered with PA-824. The outcome measures planned are: The primary outcome parameters will be: The rate in change in time to sputum culture positivity (TTP) through 8 weeks in the MGIT culture system in patients treated with: a. a combination of PA-824, moxifloxacin and PZA b. PA-824 plus Category IV regimen of RNTCP c. Category IV regimen of RNTCP Secondary outcome measures will be: 1. The proportion of patients who attain sputum culture conversion to negative at 8 weeks of treatment with: a. a combination of PA-824, moxifloxacin and PZA b. PA-824 plus Category IV regimen of RNTCP c. Category IV regimen of RNTCP 2. Time to sputum culture conversion from positive to negative in the Mycobacterial Growth Indicator Tube (MGIT) culture system (defined as the interval between the date of treatment initiation and the date of acquisition of the first of at least two consecutive negative weekly cultures) in patients treated with: a. a combination of PA-824, moxifloxacin and PZA

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b. PA-824 plus Category IV regimen of RNTCP c. Category IV regimen of RNTCP 3. The proportion of patients with Grade III or IV drug adverse events in those treated with: a. a combination of PA-824, moxifloxacin and PZA b. PA-824 plus Category IV regimen of RNTCP c. Category IV regimen of RNTCP 4. The pharmacokinetic parameters of: a. PA-824 when co-administered with moxifloaxcin and PZA b. Moxifloxacin and PZA when co-administered with PA-824 c. PA-824 when co-administered with the drugs in the Category IV regimen of RNTCP. d. Drugs in the Category IV regimen of RNTCP when co- administered with PA-824. Feasibility analysis: The project has all the necessary ingredients to provide the research results; NITRD’s LRS hospital is a part of the national TB control programme and MDR patients of the DOTS plus programme will be enrolled in the study; the development expertise is being provided by scientists at CSIR-OSDD and TB Alliance through a joint steering committee; the clinical trial expertise and the expertise in treating MDR patients is the strong point of the Clinical research and treatment group at NITRD’s LRS hospital and the Clinical Research Organisation, GVK Bio has been involved in conducting trials both for TB and other infection related products.

10. Reasons for Proposing:

A. Diagnostics:

The high mortality rate due to TB in adults and children in SEAR region,

High national /regional priority

To address the MDG 6

High impact of the technologies

Availability of required infrastructure, human resources,manufacturing capacity and expertise

To meet the high demand to deploy the PoC based TB diagnostic device in primary health centre needed for the treatment regime of the TB patients

Innovative fund to give impetus to promising diagnostic candidates from preclinical research, there is need to propose the demonstration project are addressing to deal with the following objectives:

Validation and demonstration studies for generating evidence for scale up and use in health care settings

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B.Drug:

The main drivers for the project are

• Novel combination: The need to progress novel regimens- among the experimental clinical regimens for TB that have progressed through the development phase, PaMZ is the only product which envisages a novel combination. Thus an opportunity to bring to the Indian patient if successful a defined combination rather than another new single drug, the latter is the bane that the treatment community fears as the cause of fresh resistance for the new drug

• The need for a translational platform: We need to accelerate the induction of novel anti TB regimens into use as, we have a large number of MDR TB patients with an urgent need. In the absence of a platform we will be waiting several years before the regimen becomes available to the patient, the introduction of which will any way need defined clinical trials in the country.

• The plan of building multiple translational sites that can address introduction of novel treatments for neglected diseases of concern that can be progressed after obtaining regulatory clearances in India.

11. Who could potentially develop the technology/carry out the research?

A. Diagnostics:

Several developers have expertise towards the development of molecular platform technologies, microchips etc. A Joint Venture between Bigtec Labs, Bangalore and the Tulip Group, Goa. Bigtec Labs will leverage their current IP and expertise to further development and validation of the platform and Molbio will commercialize the technology.The country has demonstrated expertise in development of chip based cartridge and modern technologies, hence, manufacturing of cartridge with various self-contained attributes could be easily performed with Public/ private organization.

Since Government has the high need to TB diagnostic device, and due to huge market demand, there will be interested parties in the manufacturing of the developed candidate device.

The goals of the project can be achieved by collaborative approach. The Center for Biodesign and Diagnostics (CBD), THSTI, Gurgaon can coordinate the consortium. THSTI has the credential to carry out multidisciplinary research and it takes care of the entire translational pathway for product development. Moreover, it has the expanding network with the medical practitioner and hospitals where the later phases of the project work can be implemented.

In India, partners could be: NIRT, AIIMS, JALMA, Lala Ram Swarup Institute of Tuberculosis and Respiratory Diseases, New Delhi; Bigtec Lab, Bangalore, Tulip group, Goa and THSTI.

Centers from SEAR countries for possible partnership:

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Name of Country Institute

Indonesia (5 following labs have reached

international performance and certified for

1st and 2nd line DST)

BBLK Surabaya, East java

Microbiology UI, Jakarta

RS Persahabatan, Jakarta

BLK Bandung, West Java

NEHCRI Makassar, South Sulawesi

Timor Leste Burnet Institute

Thailand

Chulallongkorn University,

Chiang Mai University

Canada

McGill Tuberculosis Research Group

USA

Center for TB Research Laboratory, John

Hopkins School of Medicine,

NIAID

France Institute Pasteur

UK London School of Hygiene and Tropical

Medicine

Finland Division of Biotechnology, University of

Turku

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B. Drug:

The project is envisaged with the partners described under Point 9, subheading ‘Feasibility

analysis’ under which we have described the assets and the expertise of the partners

involved. OSDD has the expertise to carry out the task. WHO would need to be a facilitator

and provide oversight. Thus at this stage of the ‘Demonstration project’ the Phase IIb clinical

trial is being planned with LRS as the main site, the key players who will carry out the

research are:

• Dr Rohit Sarin, Director, National Institute of Tuberculosis and Respiratory Diseases

formerly LRS and his team,

• CSIR-OSDD and their clinical trial team consisting of o Dr.T.S.Balganesh, Distinguished Scientist and Head OSDD. o Dr Sarala Balachandran Project Manager and Scientist OSDD. o Dr Shaheed Jawahar, Consultant OSDD. o Mr Zakir Thomas Project Director OSDD. o Dr Sudhakar Bangera, Head, CDSA, DBT. o GVK Bio and their team. All the regulatory and statutory clearances for the programme will be obtained from the

appropriate agencies / committees.

The project envisages extending the Phase IIb clinical trial to at least one more site in the near future to expedite the current trial but multiple such platforms need to be built with varying degree of infrastructure and expertise to successfully carry out Phase III programmes. 12. Who could potentially manufacture the final product?

A. Diagnostics:

The companies specialized in diagnostic device manufacturing sector will be the potential partner to manufacture the final producte.g The Bigtec, Molbio, Tulip Group etc for the diagnostics.

B. Drug:

The paramount criteria driving the selection of the manufacturing and marketing partner(s) would be ability to keep the prices affordable, robust quality and ability to access various geographic parts of the country. The regimen that is being trialled under the ‘demonstration project’ umbrella is expected to be licensed on a royalty free basis and on a non- exclusive basis to the generic drug manufacturers. This will allow ‘affordability’ through market competition as well because of the risk buffering approach pioneered through the CSIR-OSDD approach, the cost of the development being underwritten by funding from WHO or other agencies.

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13. What could be the role of WHO if any, in this demonstration project to bring the venture to fruition?

A. Diagnostics:

WHO need to be a facilitator including facilities with Government agencies, getting various stakeholders on board with respect to the need for the project progression and also, validation of new diagnostics. Once the product is developed and shows efficient diagnosis with good specificity and sensitivity and is cost effective, WHO can facilitate for the fast track approval/ prequalification of diagnostics and products developed under this project. WHO has to provide technical and operational support to distribute the product to other regions and developing countries along with Indian Government to the other regional countries.

B. Drug:

The current project proposal is to bring about a paradigm shift from the way drugs for TB have been previously discovered and developed which is adding one new drug at a time to the existing regimen. This conventional thinking cannot be anymore viable in the test case of MDR TB where the main players in the current regimen are no longer active and it is well known that the agents in the second line are either discarded or cumbersome to use agents. This thus emphasizes the need for creating novel regimen, a concept, which WHO will have to endorse in principle. What should be best new combination suitable for the treatment of MDR TB will have to analysed from multiple angles including the current usage pattern. What the project in its expanded form and in the demonstration stage purports to provide a platform where such studies can be carried out. The programme would thus need discussions with WHO experts on the best way forward for taking the current test regimen if successful, as well as advice on positioning such new regimen.

The expertise available in WHO for creation of infrastructure and other facilities for the translational platform in hospitals will add value. The expertise of WHO is also required to train doctors and paramedics involved in the clinical trials.

14. Please outline a timeframe and projected milestones for the project covering first five years. This should also highlight the immediate actions that need to be taken?

A. Diagnostics:

The project will concentrate on: Modified PCR system within three years

For the short term (modification of existing high promising lead diagnostics) refinement procedure:

Milestones - R & D Phase Year I Year II

Year III

Year IV

Year V

Total automation of specimen processing in the micro PCR

√

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machine

Inclusion of drug resistance platform √

Creation of a sample to result system

√

Establishment of consortium, assignment of responsibilities through MoUs

√

Design & manufacturing of Kit √

Automated sample prep version & the integrated version need to undergo evaluation studies in India

√

Multi country validation study √

Regulatory Approval √

B. Drug:

First year:

• Develop competency at the trial site, Obtain regulatory clearances and initiate trial. • Includes development of infrastructure at the trial site and training personnel; • Includes stream lining various technologies that are being planned to be implemented as a part of the trial. • Includes making sure that the ‘supplementary clinical services’ required for the trial are in place. Initiate the necessary action to evaluate feasibility of building another clinical trial site with the necessary platform and bring it on line. Second year- Continue the clinical trial as described in the protocol. • The project being an open label study, early patterns can be evaluated. Based on the same start bridging studies to be able to conduct Phase III trials with the current regimen under investigation.

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• An interim analysis mid way through the trial willasses the trends of the trial which would be Milestone 1. Third year- Analyse the results and make necessary recommendations.

• Milestone 2- Stop/go on proceeding to Phase III. • Milestone 2a- if results of Phase IIb clearly demonstrate significant benefit to the MDT TB patient apply to the Govt. of India for clearances to be used while Phase III is being conducted. • Design Phase III trial and obtain necessary regulatory clearances. • Choose multiple sites suitable for the Phase III trials. Fourth year:

• Examine feasibility and need for testing ‘other novel combinations’ for Phase II using the available platforms. o Obtain appropriate regulatory clearances and initiate Phase II studies. Milestone 3. • Initiate Phase III trials with the regimen that has completed Phase IIb.- Milestone 4. Fifth year: • Continue with Phase III trials. • Initiate discussions of using the developed platforms for other neglected disease, build the necessary infrastructure and expertise. Milestone 5. 15. What is the Intellectual Property landscape relative to this project? Is there any IP , e.g. patents that need to be licensed in to be able to develop and market the product in developing countries? How would IP and related intellectual assets, including knowhow, proposed to be managed in this project? A. Diagnostics: India has relevant IP on molecular primers for TB detection and sample preparation. The patenting issue arising in the future can be addressed through the Biotechnology Industry Research Advisory Council, an enterprise of DBT which is very well versed in house expertise on the IP related issues. B. Drug: For the demonstration project IP and the related knowhow has been licensed in by OSDD to develop the drug and to manufacture it. The drugs will be sold without charging any royalty on sale. The development will be derisked by OSDD by sponsoring the trials. The expenditure upto regulatory clearance will be met by OSDD. If the drug fails the risk will be that of OSDD. If it obtains regulatory clearance, the drug will be licensed to generic manufacturers on a non exclusive basis as explained in response to 12. There is no Intellectual Property constraint on immediate operationalization on the demonstration project. OSDD has the licensing skills to negotiate licenses to other

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developing countries and the technical competence to see through the development phase upto the clinical trials. OSDD treats the drug development as an IP neutral, pre-competitive activity. OSDD is not expecting return on investment and will not charge any royalty from the manufacturers and will license the drug non exclusively to facilitate generic manufacture and competition in the market place which will make the drugs affordable and accessible. The drug developed by OSDD will be available without royalty to the developing world. The reason for not charging royalty is multifold. It reduces ultimate cost of the drug. It also factors in the fact that public funds have already been used for development of the drugs. In most developing countries TB drugs are administered through government agencies who are the purchaser of the drugs. Charging royalty on the drugs developed out of public funds which will be purchased by public exchequer will only be meaningless. This approach will remove all IP constraints from development and manufacture of drugs. 16. *What would be the strategy to ensure access to the product once it is developed?

A. Diagnostics:

Data on performance strategy of the diagnostic technology would be generated through this project, which could be considered for the fast track approval from WHO. The technology would be developed by a companyfrom resource limited settings and would ensure the accessibility in these settings.

De-linkage of R&D cost from product cost:The R&D cost would be de-linked from the product cost, which will ensure a cost effective final product and therefore greater affordability.The product will be reasonably priced and the Revised National Tuberculosis Control Program price could be discussed based on volume commitments. Alternative strategies which are already adopted to reduce GeneXpert prices could be explored to further reduce the cost. Bulk Procurement: The final product is meant to be introduced into the public health systembased on the performance criteria and the involvement of the Ministry of Health on board will provide the assurance that this diagnostic test, will be utilized in the national program. Hence, the diagnostic kit will be bulk-procured for streamlined supply to the public health system. Advance Market Commitment: The final product will be introduced in the public health system, hence, the Governments need to provide assurance, in the form of an advance market commitment (AMC) about the certain volume of product to be utilized by the public sector. Therefore, the manufacturer of the product would be assured about the sustainability of its product. Dispensing: The diagnostic device need to be dispensed through primary health centers and “last mile” delivery will be mediated by Accredited Social Health Activists (ASHAs), who have been instrumental in the National Rural Health Mission of the Govt. of India. Similar kind of approach may be followed in other regional countries. Also, the device would be introduced in the referral system too where the drug resistance test will be useful.

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B. Drug:

The strategy is to derisk the development phase by setting up a platform by developing clinical trial infrastructure and trained manpower for conducting clinical trials capable of conducting clinical trial in complex disease like TB in multiple sites. The drug development cost has to be met out of public funds. Once developed, the regulatory clearances will be obtained by OSDD to manufacture the drug.

The strategy to ensure access to the product is to utilize the existing generic drug industry business model to deliver the drugs to the market. The development including regulatory clearance will be obtained by OSDD. Upto the regulatory clearance the OSDD approach is IP neutral. After regulatory clearance manufacturing partners will be identified.

The paramount criteria driving the selection of the manufacturing and marketing partner(s) would be ability to keep the prices affordable, robust quality and ability to access various geographic parts of the country. The regimen that is being trialled under the ‘demonstration project’ umbrella is expected to be licensed on a royalty free basis and on a non- exclusive basis to the generic drug manufacturers. This will allow ‘affordability’ through market competition as well because of the risk buffering approach pioneered through the OSDD approach. The competition in the market among multiple manufacturers will make the drug accessible to patients. The cost of the development is proposed to be underwritten by funding from WHO or other agencies.

17. How could the project be financed paying particular attention to the need to demonstrate new and innovative forms of financing? Also provide an estimated cost of the project.

A. Diagnostics:

Development Item Budget (INR) Timeline

Sample prep automation productization

3,90,00,000 Version 1: Single MTB Cartridge: Year 1

Version 2: 4 Randomly accessible MTB Sample Prep Cartridges: year 1

Inclusion of drug resistance protocol: year 1

Sample to result platform 10,00,00,000 Year 2

Multicentric in-country validation

30,00,000 per site x 5 sites = 1,50,00,000

Year 3

Multicentric inter regional 5,00,00,000 Year 3

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country validation

Different methods of financing including grants and soft loans from the scientific funding establishment in India and philanthropic agencies need to be explored for this purpose.

B. Drug:

At the heart of the proposal is reduction in cost of conduct of clinical trials through optimal use of existing investments in hospital and other infrastructure by public funded agencies. National governments have invested considerably in hospital infrastructure to administer the national programmes such as Revised National TB Control Porgramme (RNTCP) or the National Malaria Control Programme of India. But these are not optimized to conduct clinical trials. The proposal is to invest in setting up bridging infrastructure to conduct clinical trials, infuse technology and to develop skills by training the personnel to conduct clinical trials at globally acceptable standards.

The proposed Phase IIb clinical trial will be conducted by OSDD at one site for which it has sought funds from government of India. With the WHO funding support multiple trial sites can be developed which will speed up the conduct of trails and ready the country to take up multiple trials.

The entire development cost upto regulatory clearances are proposed to be met by public funding. This approach de risks the drug development cost for any entity which develops drugs. The trail site platforms developed will be available for any organization to develop drugs. The funds for conduct of the trails should be available from a common source. The technical support and advice for conduct of trials will be available from OSDD or specialized organization like THSTI. These organisations are public funded and have expertise in drug development of neglected diseases.

The use of existing public funded institutions is expected to lower the cost of clinical trials. The following estimate of the proposed Phase IIb trial show that the trials can be conducted at affordable costs.

The cost of conduct of the proposed Phase IIb Trial of the novel drug combination discussed in this proposal includes: i. Cost of setting up bridging infrastructure and providing technologies to the Investigator; ii. Cost of the investigator in conduct of the trials; iii. cost of drugs; iv. insurance and related costs; v. Cost of the Clinical Research Organisation The above costs have been firmed up in the proposed trial and are expected to be around Rs 20 Crore (about US$ 3.5 Million) for 200 patients. Per patient cost works out to be Rs 10 lakhs (about US$ 18,000). It is estimated from experience that if this trial for about 200 patients is conducted elsewhere, it will cost about US$ 70 million to 100 million putting the per patient cost at about US$ 300,000. This is also inclusive of the ‘one time’ infrastructure and expertise development costs at one site where the inducted infrastructure would be

27

available for multiple trials and thus significant reduction even in this cost is anticipated in the long run.

The ultimate benefit of reduction in cost will be with the patient as the proposal is to derisk the development of drugs and license it for manufacture without charging royalty.

18. How could the project be governed and coordinated paying particular attention to the need to demonstrate better way of coordination?

A. Diagnostics:

A dedicated International Scientific Advisory Board with expertise in the respective domain may be created for the governance and coordination of the project which will meet in regular intervals and monitor the progress and suggest modification.Governance and co-ordination of this consortium will be spear-headed by WHO and will nominate different experts from world over to provide hand-holding in different phases of development, manufacture and deployment.

The multiple partners in each stage of development will report to their respective advisory groups which will play a key role in go- no -go decision in each step.

These expert groups will include members from FIND and country MoH also which will help the consortium to take decisions during deployment of the diagnostic.

B. Drug:

Please see response to point 11. The project has brought together various governmental and non-governmental entities and private sector organisations with expertise in conduct of clinical trials. The demonstration project is coordinated by OSDD at various levels which include an independent Steering committee of experts, Institutional Ethics Committee as well as a Scientific Advisory Group, which has the expertise and skilled leadership competent to handle projects involving extensive coordination among multiple partners. A joint steering committee of OSDD and TB Alliance will channel the learning from other trial sites into this project.

19. Have any donor agencies/ Governments already indicated interest in supporting the project?

A. Diagnostics:

Indian funding agencies like DBT, CSIRand the respective Industries have already funded jointly to develop the initial product. Project support for additional R & D may be partially financially supported by one of the schemes of the public funding agencies. The proposed demonstration project couldattract inter country pooled investment from the regional countries and other donors through WHO for further R& D and validation.

B. Drug:

OSDD programme funded by the Government of India has committed to support the Phase IIb trials at one location. This will serve as a demonstration of feasibility of the proposed

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project. However, the project has to be scaled up to multiple locations, for which additional funding will be required.

References:

1. Global Tuberculosis Report, 2013, WHO 2. DEFINING DISEASE TYPES I, II AND III. Background document provided by the WHO

Secretariat, 14 November 2012. 3. WHO: Tuberculosis Fact sheet N°104". World Health Organization. November 2010.

Retrieved 26 July 2011 4. Diagnosis: Waiting for results, Catherine de Lange, Nature 502, S10–S12, 10

October 2013 5. Robust, reliable and resilient: designing molecular tuberculosis tests for microscopy

centers in developing countries. C .Denkinger, S. V kik, M. Pai, Expert Rev. Mol. Diagn. 13(8), 763–767, 2013

6. Rapid diagnosis of Mycobacterium tuberculosis with Truenat TB: A near care approach. C. Nikkam et al; PLOS One, Vol.8, iss. 1, Jan 2013.

7. Utility of Universal sample processing methodology, combining smear microscopy, culture, and PCR, for diagnosis of Pulmonary tuberculosis. S. Chakraborty, M. Dudeja, M. Hanif , J. S. Tyagi, J Clin Microbiol, 43 (6): 2703-8, June 2005

8. Scientists plan to unveil hand-held e-nose to detect TB. Times of India, Nov 16, 2011, 03.

9. Achira weaves microfluidics into diagnostics. Biospectrum, 23 May, 2012 10. The Global Plan to Stop TB, 2011–2015. Geneva, World Health Organization, 2010

(WHO/HTM/STB/2010.2). Available at:http://www.stoptb.org/assets/documents/global/plan/TB_GlobalPlanToStopTB2011-015.pdf

11. Tiered laboratory capacity for TB control in resource-constrained health-care settings in relation to the location and sophistication of laboratory tests employed and patient access. WHO. Diagnostics for Tuberculosis: Global Demand and Market Potential. 2006.

12. Point of Care tests for diagnosing infections in the developing world, R. W. Peeling and D Mabey, Clin Microbiol Infect, 16:1062-69, 2010;

13. Mapping the landscape of diagnostics for sexually transmitted infections. H. Kettler, K. White, S. Hawkes. Geneva: WHO/TDR, 2004.

14. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. A. H. Diacon et al, Lancet. 2012 Sep 15; 380 (9846):986-93.

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Annexure- I

The “ASSURED” Criteria for ideal rapid diagnostic test

A= Affordable

S= Sensitive

S= Specific

U= User Friendly (simple to perform in a few steps with minimal training)

R= Robust and Rapid (can be stored at room temperature and results available in < 30 minutes)

E= Equipment free or minimal equipment that can be solar powered

D= deliverable to those who need them