Beyond The Ban

Almost a year after the World Health Organization (WHO) issued a rare ‘negative’ policy recommendation urging countries to ban the use of antibody-based test kits for active tuberculosis (TB) detection, India’s Ministry of Health & Family Welfare became the first – and so far the only – country to issue a notification banning the manufacture, sale, distribution, use and import of such serodiagnostic kits.

WHO’s recommendation in July last year came after a year of rigorous analysis of evidence by WHO and global experts. 94 studies were evaluated – 67 for pulmonary TB (TB in the lungs) and 27 for extra-pulmonary TB (TB elsewhere in other organs). Overwhelming evidence showed that the blood tests produced an unacceptable level of wrong results – false-positives or false-negatives – relative to tests endorsed by WHO.

For a country saddled with an estimated one fifth of the global burden of TB cases, with some estimates putting a total of 9.2 million new cases and 1.7 million deaths every year, proper TB diagnosis could go a long way to controlling the spread of this highly communicable disease.

Thus it is no wonder that TB detection/ diagnosis and treatment is top priority of India’s Ministry of Health & Family Welfare. In fact, ‘universal access to quality TB care for all TB patients’ is the objective of the Revised National Tuberculosis Control Programme (RNTCP) which aims at detecting and successfully treating 90 per cent of all TB cases by 2015. This Programme has seen substantial infusion of funds over the past 13 years since its implementation, and there have been success stories as well. A total of Rs 1447 crore has been allocated for the 11th Five year plan by the Planning Commission. (See BOX: Vital stats of India’s TB control programme)

“This ban will greatly improve patient diagnosis and reduce costs for both patients and health services in India.” Dr Karin Weyer Coordinator, Diagnostics Laboratories & Drug Resistance Stop TB Department World Health Organization

Dr Karin Weyer, Coordinator, Diagnostics, Laboratories and Drug Resistance, Stop TB Department, World Health Organization, hopes that this ban will greatly improve patient diagnosis and reduce costs for both patients and health services in India.

There are signs that the advisory from WHO was having the desired impact, even before the Government of India (GoI) ban. According to data provided by the Foundation for Innovative New Diagnostics (FIND), orders from India for GeneXpert test modules, one of the WHO recommended tests provided at concessional prices to countries like India with a high TB burden, showed a steady pick up from six modules through Q3 2010 to 96 in Q1 2012. The country clocked a total of 114 test modules for the entire period from Q3 2010 to Q1 2012.

The cost of such TB testing kits is expected to drop even further with the executive board of UNITAID recently approving funding of $30 million to scale up access to Xpert MTB/RIF which will further reduce the cost of its use. This test, an automated, cartridge-based nucleic amplification assay for the simultaneous detection of TB and rifampicin resistance directly from sputum in under two hours, is based on the GeneXpert platform. which was developed as a partnership between FIND, Cepheid Inc. and the University of Medicine and Dentistry of New Jersey, with support from the US National Institutes of Health. WHO endorsed the technology in December 2010 and is monitoring the global roll-out of the Xpert MTB/RIF test modules.

A task half done?

“WHO endorsed tests such as molecular tests and liquid cultures are quite expensive for India, especially in the private sector. Efforts are needed to extend special, reduced prices to the private sector, not just the public sector.” Dr Madhukar Pai Professor, McGill University, Canada, Co-chair, Stop TB Partnership’s New Diagnostics Working Group

But will the GoI ban really make a difference? Experts in the field like Dr Madhukar Pai, Professor, Dept of Epidemiology & Biostatistics, McGill University, Montreal, Canada; and Co-chair, Stop TB Partnership’s New Diagnostics Working Group feel that the WHO endorsed tests, such as molecular tests and liquid cultures are quite expensive for India, especially in the private sector. He feels efforts are needed to extend special, reduced prices to the private sector, not just the public sector.

“If import duty on the TB molecular biology test is waived, as also the duties on other imported TB test kits, this ban will serve its purpose of patients having a viable alternative to turn to.” Ameera Shah Mng. Director & CEO, Metropolis Healthcare

Ameera Shah, Managing Director and Chief Executive Officer, Metropolis Healthcare, takes the argument a step ahead. She says that though the GoI has gone ahead and banned the antibody test, it should have also provided an alternative. Of the tests giving more specificity, the sputum-based tests, the culture-based test takes up to six weeks to give results while the alternative test, the molecular biology test, costs around Rs 1,500—Rs 2,000, thanks to a 27 per cent customs duty. This is obviously too expensive for most patients in India.

Shah makes the point that if this import duty on the TB molecular biology test is waived, as also the duties on other imported TB test kits, this ban will serve its purpose of patients having a viable alternative to turn to.

And a viable alternative is definitely the need of the hour. Jayant Singh, Industry Manager, Healthcare Practice, South Asia and Middle East, Frost & Sullivan says that the number of tests being done to diagnose TB is about 20 to 22 lakh per year but the fact that most of these tests are not accurate in terms of sensitivity and specificity, pose even greater problems.

“We need to see the bigger picture. A wrong treatment leading to drug resistance TB and spreading it further is more disastrous for society than patients not diagnosed and not treated.” Jayant Singh Industry Manager Healthcare Practice South Asia and Middle East Frost & Sullivan

Expanding on the problem, Singh says that the microscopy test tends to detect not more than 35 per cent of the cases, a chest X-ray is only useful for pulmonary TB and serological tests tend to give a lot of false positive results.

With microscopy and chest X-ray, a lot of positive cases are left out (false negatives) and with serological tests, a lot of negative cases are reported as positive (false positives). Both situations are dangerous as in the first case, the infection is not controlled because of undiagnosed and untreated cases while false positives leads to misuse of Anti TB Therapy (ATT) due to which antibiotic resistance sets in leading to the more dangerous form of TB: MDR (Multi Drug Resistant) TB. MDR TB cannot be treated by standard TB drugs and the cost of treatment also goes up, says Singh spelling out a scenario which is already playing out in India. Another factor leading to MDR TB is incomplete course of therapy as patients tend to stop taking the drug after the first three-four months once they get partial relief from the symptoms.

“The only and best option is to open as many culture centres as possible and detect TB using the microbiology techniques,” advocates Singh.

“Various clinical studies have demonstrated limited clinical utility of all available TB serology kits but unless more effective diagnostic tools are available, serological assays for difficult-to-diagnose infectious diseases like TB will continue to be used.” Dr B R Das President – Research & Innovation, Super Religare Laboratories

As Dr BR Das, President—Research & Innovation, Super Religare Laboratories (SRL) points out, various clinical studies have convincingly demonstrated limited clinical utility of all available TB serology kits but unless more effective diagnostic tools are available, serological assays for difficult-to-diagnose infectious diseases like TB will continue to be used.

Physician power

“There is a need for doctor education so that doctors can steer the patient towards the right diagnostic and therapeutic solutions.” Rajeev Kumria Head Business Development, Transasia Biomedicals

The role of the physician in controling TB infection cannot be ignored. ”The role of physicians is primordial”, says Rajeev Kumria, Head Business Development, Transasia Biomedicals, “as it is the physician who makes the decision for choosing diagnostics and therapeutics. The physician guides and counsels patients depending upon the clinical conditions to recommend the right type of diagnostic test subsequently leading to correct therapy.” His observation is that physicians sometimes recommend wrong tests, either due to lack of information on the latest tests or lack of availability of other better alternatives. Therefore he feels there is a need for doctors to be educated on these factors so that they can steer the patient towards the right diagnostic and therapeutic solutions.

Similarly, Das says physicians can counsel patients to provide site specific specimens such as sputum for pulmonary cases instead of blood which invariably is expected to provide incorrect results.

So it seems that the GoI ban will not really have the desired results unless physicians stop prescribing the banned tests. Singh warns that we need to see the “bigger” picture — a wrong treatment leading to drug resistance TB and spreading it further is more disastrous for society than patients not diagnosed and not treated. Though either of the scenarios are acceptable, he opines that if forced to make a choice, then not using serological tests is a better choice than using it.

What the GoI can do is make the WHO-prescribed tests cheaper and thus more accessible by reducing or scrapping custom duties on imported tests. As Pai says, a good TB test should be considered “life-saving” for duty exemption. It thus goes without saying that import duty exemption on such TB test kits will help prevent thousands of TB related deaths every year.

But besides government action, industry too can and must chip in. As Pai points out, diagnostics manufacturers must also realise that most TB patients in India, even those in the private sector, are poor, and unless prices are reduced, good TB tests will remain unaffordable to them. The fact that the advanced test need to be imported also indicates the lack of innovative disease diagnosis kits made in India. Kumria states that the Indian industry is primarily involved in design and manufacturing of cost mass base screening test devices and instruments. Listing the underlying reasons for this sad state of affairs, he says, “The Indian university culture is also not entirely in sync with the global practices which boost innovation and entrepreneurship among qualified students.”

Kumria notes that a part of the pharma, biotech, healthcare industry are pure R&D companies which get easy funding to innovate and then get either sold to larger companies or sell/license the technologies. Within this realm are individual innovations from young scientists who are encouraged to innovate and start their own companies straight out of university after Ph.D’s. Most of the successful scientists in developed world are also successful entrepreneurs. This is not so in India and it needs to change, urges Kumria.

Hopefully this dismal situation could change soon. Last year, Pai had helped organise the first ever conference on TB diagnostics in India, which focused on the need to develop innovative TB diagnostics. He indicates that since the meeting in Bangalore in 2011, Indian companies have begun developing more affordable molecular TB tests, although none are on the market as yet. Pai hopes these tests will be shown to be valid and accurate and can be scaled up within India as a replacement for serological tests.

Thus it seems logical that both the government, the diagnostics industry as well as the physician fraternity will need to walk that extra mile if they are really committed to curb the TB epidemic in India.

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