1. Introduction

While serological tests work well for several infectious diseases, existing serological tests for tuberculosis [TB] (both ELISA and rapid lateral flow tests) are not accurate or consistent enough to be useful, as shown by a 2007 meta-analysis [1] and confirmed by an independent evaluation of 19 commercial rapid tests by the World Health Organization (WHO) the following year [2]. Unfortunately, the evidence from these studies was not translated into policy at that time.

While most regulatory bodies have mechanisms to withdraw or ban dangerous drugs and vaccines, there is little awareness about the human and economic consequences of bad diagnostics [3]. Another reason for the initial inaction was possibly the perception that these tests were rarely used. In reality, these tests are widely abused in the private sector in countries such as India, with at least 1.5 million serological tests performed in India every year [4].

Every major private laboratory in India offers TB serological tests, mostly ELISA kits imported from developed countries that do not allow these tests to be used on their own TB patients. The problem extends far beyond India. These tests are available in the private sector in at least 17 of the 22 highest TB-burden countries, from China to South Africa to Afghanistan [4].

In 2010, WHO recognized this widespread problem and convened an Expert Group to formulate a policy. The Expert Group considered an updated meta-analysis of test performance and a cost-effectiveness analysis. The meta-analysis synthesized evidence from 92 studies and concluded that commercial serological tests remain inconsistent and inaccurate, supported only by data of very low quality [5]. The cost-effectiveness study found that serology results in more human suffering, secondary infections, and false-positive diagnoses than sputum smear microscopy, while increasing per-patient costs to the Indian TB control sector [6]. At $10–$30 per test, the costs of testing (often borne by patients who pay out-of-pocket), plus the cost of TB drugs wasted on treating patients with false-positive results, rival the entire Revised National TB Control Programme (RNTCP) annual budget of $65 million.

Based on this evidence, the WHO released a policy on 20 July 2011 concluding that since “the harms/risks [of commercial serodiagnostic tests] far outweigh any potential benefits (strong recommendation)...these tests should not be used on individuals suspected of active pulmonary or extra-pulmonary TB, irrespective of their HIV status [7]”.

While the WHO policy provides global guidance, it is up to high-burden countries to implement this policy. Immediately following the WHO policy announcement, the Indian RNTCP issued an advisory against TB serological tests, endorsing the WHO policy recommendations [8]. The challenge, however, is the Indian private sector, which manages nearly half of all TB cases in India [9].

It is well known that TB management practices in the private sector vary widely, often deviating from national and international standards [10–15]. For example, private providers in India are known to underuse sputum smears, and overuse chest X-rays and serological tests for active TB detection [11,14,16–18]. Prescription studies and TB drug market analyses show use of irrational drug regimens, significant overuse of TB drugs, and easy access to TB drugs over-the-counter, without prescriptions [10,13,19,20].

In this context, the following research will explore why serological tests are so popular in the private sector and what factors have paved the way for their widespread use. The lessons learned from the serology story can be applied to validated, WHO-endorsed technologies that need to be scaled-up.

2. Materials and methods

3. Results

3.1. Quantitative analysis of interviews

Fig. 1 summarizes the responses to the question: “Why is ELISA (TB serological test) the major test for TB in the private sector? Could you list all possible reasons?” Overall, a lack of awareness among doctors regarding TB diagnosis was the most frequently given reason. This was formulated either as “doctors’ ignorance” about the lack of accuracy of serological tests, or by pointing out that RNTCP and the government had failed to educate the private doctors. This reason was followed by referral fees (incentives) which encourage the use of serodiagnostics. Doctors who request serological tests are often offered by the private laboratories about 20–50% of the price (i.e., between 150 and 300 rupees) paid by the patient. Redundant testing where serology is one component in a battery of lab tests, a lack of accurate rapid tests with sensitivity higher than sputum smear (preferably also blood-based) and patient’s affordability were some other leading reasons.

Figure 1

Bar chart showing the frequency of all replies to the question: “Why is ELISA (and other serological tests) the major test for TB in the private sector?” (N = 33 respondents with direct experience in TB diagnostics).

3.4. Root causes for the success of TB serological tests in India

The RCA analysis suggested seven root causes (Fig. 2) that can be grouped into three categories: technical/medical, economic, and regulatory.

Figure 2

Current Reality Tree which identifies the root causes of the widespread use of TB serodiagnostics in the private sector in India.

From a technical/medical perspective, RNTCP is currently underfunded and perceived to be focused only on sputum smear-positive cases. Indeed, most patients can only access sputum smears in the public sector. Private doctors therefore do not think the RNTCP can offer anything more than just smear microscopy for their patients, and they also believe that smears are not adequate for the types of cases they encounter (e.g. extrapulmonary TB and smear-negative disease). Private doctors also believe that smears are insensitive and inconvenient for patients. More importantly, TB culture facilities are not widely available via the RNTCP, and there is a general lack of trust in the quality of government-run services. Thus, private doctors are reluctant to refer their patients to RNTCP for diagnostic workup, even if it is free for patients. Also, because there is no accurate, WHO-endorsed, simple point-of-care test for TB, serological tests meet a perceived need among doctors for a rapid, blood-based test, especially for extrapulmonary TB, smear-negative TB, and for investigation of chronic fevers and relevant conditions (e.g. infertility in women).

From an economic perspective, several players are given incentives to use serological tests along the value chain, and this sustains their market. In contrast, there are no affordable molecular or liquid culture tests on the Indian market. This means such tests are mostly imported and are very expensive for Indian patients. Indeed, tests such as automated liquid culture (e.g. MGIT 960, BD, Sparks, USA) and molecular tests (e.g. Xpert MTB/RIF, Cepheid Inc., Sunnyvale, CA, USA) cost as much as $50–$100 in the private market, and these tests are rarely used because of the high costs. In this context, serology is perceived by doctors as a “more affordable and convenient” alternative.

From a regulatory perspective, because private medical care is poorly regulated, doctors in the private sector are outside the scope of RNTCP and do not feel compelled to follow RNTCP guidelines. Apart from the RNTCP guidelines, there are no other national TB guidelines for private doctors to follow. While the International Standards for TB Care are available [15] and endorsed by the RNTCP, there is no easy mechanism to implement or mandate them in the private sector. In the past, Indian doctors were not required to get re-certified or even undergo continuing medical education (CME) to keep up-to-date with the latest guidelines. This may be changing with the Medical Council of India (MCI) proposing new rules that require mandatory CME credit hours to maintain their registration. For many private doctors, a major source of educational material is material handed out by pharmaceutical and laboratory sales representatives. Thus, some private doctors may be genuinely unaware that serological TB tests are not recommended by any agency. They may be using these tests in good faith, and not necessarily driven by economic incentives.

Regulation of in vitro diagnostics (IVDs) is weak in India. The Central Drugs Standard Control Organization (CDSCO) classifies IVDs as “critical” or “non-critical” with only a few tests (e.g. HIV, hepatitis B & C) related to blood safety (in blood banking) considered “critical”. TB tests are not classified as “critical tests” by the Drug Controller General of India (DCGI), and this allows for entry and sale of suboptimal serodiagnostics with very little independent validation [18]. In fact, a large number of imported and domestic serological kits are readily available in the market and various players have incentives to use them [4,6]. Many of the kits on the market claim to have near-perfect sensitivity and specificity, without published data to support such claims [5,6].

Lastly, the private laboratory testing market in India is also poorly regulated. A majority of Indian labs are not accredited or certified by a quality assurance body [18], and there are few requirements for establishing and running laboratories, although this may improve with the enforcement of the Clinical Establishments Act [26]. There is no transparency in pricing, and practices such as referral fees are well documented [27].

4. Discussion

Mismanagement of TB is bad for the individual patient. For example, false-positive diagnoses result in unnecessary drug treatment and side effects, personal financial losses, and public resource utilization [6]. Mismanagement is equally bad from a public health perspective because every mismanaged or undiagnosed TB patient serves as a source for new infections in the community [3]. Widespread abuse of inappropriate tests can prevent the use of good diagnostics, and this is a major challenge for implementation of new diagnostics. In a country where private out-of-pocket expenditure dominates the financing of health care costs and where such spending is one of the major reasons for people sliding into indebtedness [28], the use of inaccurate tests might have a negative impact on household budgets of many people.

For each of the root causes identified, several recommendations are suggested (Table 3). Strengthening the RNTCP, increasing its budget, and scaling-up new, validated diagnostics within RNTCP will enable more Indian TB patients to get quality-assured diagnostic work-up, and might help address the perceived need of doctors for improved diagnostic tests. Because expanding DOTS coverage and engaging all providers is critical for RNTCP, the programme should make an effort to understand why patients prefer the private sector, and why so many doctors keep referring patients to private diagnostic laboratories and not to the RNTCP. Lack of trust in quality of public services and limited availability of diagnostics other than sputum smears are issues which the RNTCP can and must address.

Indeed, India’s annual healthcare spending continues to remain one of the lowest in the world. Not surprisingly, the RNTCP budget is low, even though modeling suggests that TB control has been a very cost-effective strategy for improving the health status of India’s population, with exceptional return on investment from a societal perspective [29]. It has been estimated that the scale-up of TB control in India accounted for just 1.0% of public expenditure on health over the period 1997–2006 [29]. Thus, the RNTCP’s current low budget does not allow widespread scale-up of sophisticated, WHO-endorsed technologies. For example, only a small fraction of Indian patients has access to liquid cultures and line probe assays. In 2010, India, together with DR Congo and Bangladesh, had the poorest access to culture facilities among high-burden countries (less than 0.1 per 5 million of population) [30]. A large proportion of TB patients therefore end up seeking private medical care, even if it meant higher expense for patients who mostly pay out-of-pocket [9].

The RNTCP has clearly made great progress in the past decade and has successfully scaled-up the DOTS strategy to cover 100% of the Indian population [29]. The program is currently preparing to enter a new phase, the National Strategic Plan (NSP), for the period 2012–2017. For this new phase, significantly higher budgets have been requested. Scale-up of new diagnostics is a central part of this plan, along with greater engagement of the private sector, which must be involved in creating RNTCP guidelines, and thereby have greater ownership. Creation of an “Indian Standards for TB Care,” along the lines of the “International Standards for TB Care”, for both public and private sectors, might help in overcoming the reluctance of private doctors to follow RNTCP guidelines, which they do not perceive as their own.

The central issue to appreciate is that India has the largest private health sector in the world, with 60–80% of health care sought in the private sector, and a health care market that is worth billions of rupees [31]. Despite its enormous size and importance, this sector is largely unregulated [31], although the Clinical Establishment Act 2010 attempts to address this tricky and controversial issue [26]. This Act is yet to be implemented and has been opposed by the private medical sector in India [32]. Full implementation of this Act should be a major priority for the Indian government and ministry of health.

Furthermore, the private health care market in India is heavily doctor-centric. The doctor is the sole decision maker in determining the tests that a patient will receive. While not all private doctors accept kickbacks and order unnecessary tests, the private healthcare system is influenced by monetary gains, with wide variations in practice quality [20–23]. Thus, any potential solution must address this reality, and take into account well-documented issues such as referral fees [27,33], unnecessary interventions [34], and widespread antibiotic abuse [20,35,36].

TB serological tests can bring economic benefits to doctors, although not all laboratories offer incentives and not all doctors accept incentives. Similar profit to doctors must be assured for good practice. This could be a referral fee paid to them by RNTCP for referral to their facility or to an accredited private laboratory which only performs WHO-endorsed tests. Further, free DOTS medicines could be made available to patients in the private sector so that doctors do not need to be concerned about losing their patients to the RNTCP.

The government should actively educate the public on the prevalence of referral fees in the private laboratory sector and empower patients to choose service providers. For that, patients must be enabled to judge laboratory quality on their own and make their choice based on quality and price. They must be aware of the accreditation of laboratories and must have a reasonable choice of accredited laboratories. Only then fair price competition among laboratories can be promoted.

Unfortunately, there is currently no way for patients to get data on quality of laboratories or doctors or hospitals in India. There is no objective metric or ranking system to judge quality of medical care in the country. Quality Council of India [37], an autonomous body of the Department of Industrial Policy and Promotion, Govt. of India, must address this by establishing and improving national accreditation structures, including National Accreditation Board for Testing and Calibration Laboratories (NABL), and National Accreditation Board for Hospitals and Healthcare Providers (NABH).

A majority of Indian laboratories are not accredited or certified by a quality assurance body [18]. Currently, less than 250 Indian laboratories out of an estimated 50,000 have NABL accreditation [38]. There are very few requirements as to minimal training qualifications for persons performing laboratory procedures, and skilled laboratory technicians are scarce in India. Making NABL accreditation a mandatory requirement for all laboratories is a policy worth consideration.

In the current scenario where regulation of IVDs is virtually limited to the so-called “critical devices” listed by CDSCO, putting TB tests on this list is essential to remove serological TB tests from the market. In principle, the recent WHO policy would make this regulatory action straightforward. In practice, it will require political will at the level of the DCGI, high-level support from agencies such as RNTCP and Indian Council of Medical Research, and advocacy from patient representatives, civil society and consumer groups.

If a new diagnostic is to succeed in the Indian private market, what characteristics should it have? Based on the lessons learned in this analysis, we think the new diagnostic should provide rapid results (e.g. same-day diagnosis), be more sensitive than sputum microscopy, work well with specimens other than sputum (e.g. blood or urine), and be able to detect extrapulmonary and smear-negative disease (Table 4). The test should not be too cheap or too expensive, but rather be in the middle range of about Rupees 500 [approximately US $10] (price to the patient) in the private sector, and the new test should not force labs to make big investments in equipment, maintenance or training.

5. Conclusion

Although the WHO recommendation is a major progress in advocating against the use of inaccurate TB tests, the WHO policy, by itself, is unlikely to change the reality in the Indian private sector. A clear understanding of the ground realities and the root causes should facilitate market-based strategies that can help replace serological tests with accurate, validated tools. Our analysis suggests that increased funding for TB control, scale-up new diagnostics via the RNTCP, stronger regulation of the private healthcare sector (including improved regulation of TB diagnostics), rapid development of in-country R&D to bring new diagnostic options to the market, and greater engagement of the private health sector with the RNTCP are critical ingredients for success.

Author contributions

Szymon Jaroslawski and Madhukar Pai conceived and designed the study. Jaroslawski conducted the key informant interviews, analyzed the data and wrote the first draft of the manuscript. Pai provided input in the data analysis and interpretation, and edited and revised the manuscript for important intellectual content. Both authors have approved the final article and agree with its contents.

Conflicts of interest

None of the authors have any financial/industry conflicts to declare. Szymon Jaroslawski works on research projects co-financed by the Institut Merieux, France. Madhukar Pai was engaged in the WHO policy recommendation against serological tests and has published meta-analyses and cost-effectiveness studies on TB serological tests. He serves as a consultant to the Bill & Melinda Gates Foundation (BMGF).

Acknowledgements

We are grateful to all the key informants who generously contributed their time and expertise. We are also grateful to Karen Steingart, David Dowdy, and Andrew Ramsay for providing constructive feedback on an earlier version of this manuscript. Szymon Jaroslawski is supported by an allowance from France Volontaires, Ivry sur Seine, France. Madhukar Pai is supported by research grants from the Canadian Institutes of Health Research (CIHR), European and Developing Countries Clinical Trials Partnership (EDCTP) (TB-NEAT grant) and European Commission (EU-FP7; TBSusgent grant), and Grand Challenges Canada. These funding sources had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.