Archive for August 2011
The call for nominations for The Tuberculosis Survival Prize 2011 closes on the 30th September 2011. The prize, an annual award of $2000 sponsored by the Lilly MDR-TB Partnership, is awarded in recognition of innovation in TB/MDR-TB advocacy and social mobilization, and the winner will also be profiled on the TBSP website. Nominations are currently open for individuals, groups or NGOs working in the field of HIV/TB or TB/MDR-TB. Applications from people directly affected by TB/MDR-TB are also actively encouraged, as are those from organizations who were previously nominated for the prize.
Applicants are encouraged to complete the prize entry form on the Tuberculosis Survival Project website
(http://www.tbsurvivalproject.org/) and sent directly to firstname.lastname@example.org.
All applications should be written in either English or French, and should include a photograph of the applicant. Applications will be judged by an invited panel representative of a variety of sections of the global TB community. The prize will be presented at a reception in connection with the International Union of Tuberculosis and Lung Disease in Lille, France, 26th October 2011.
And yet, it is a known fact that India continues to have the highest burden of TB in the world and accounts for around on fifth of the global incidence. Out of 9.4 million new TB cases globally, 2 million are estimated to have occured in India. Around 280,000 people succumbed to TB in 2009. Why? Why are we not able to bring the situation under control, like we have say with Polio or Diptheria?
Control of TB is governed by one V and two Ds – Vaccines, Diagnosis and Drugs. And as experts say, all three are outdated. The BCG Vaccine recently celebrated its 90th anniversary; the smear microscopy test, which is still the most widely used diagnostic tool is 125 years old and the most used TB drug is over 40 years old. Additionally, serological (antibody tests) are highly innacurate, and they are still being widely misused by the private sector for diagnosis of TB. These tests are not recommended by the RNTCP or any agency. On the contrary, the WHO has issuesd alerts against the use of serological tests.
Advances in all three areas are vital but given that we already have a huge problem on hand, diagnosis and drugs have an urgent and important role to play in the control of TB. And yet, industry does not seem to be responding to the problem with the urgency that it needs to.
It was to showcase the dire need for newer and more efficient diagnostics and encourage industry to look at diagnostics as a viable business opportunity that a conference entitled “TB diagnostics in India – From importation and imitation to innovation” was held on 25 & 26 August at the St John’s Research Institute. The conference attracted an international audience that consisted of RNTCP representatives, academicians, scientists, researchers, funding agencies and members of the pharmaceutical industry.
The sessions were structured in a manner that gave opportunities for the problem to be examined through several lenses, the most important one being that of why industry should consider the R&D of diagnostics as lucrative. Numbers were projected, a business case was presented which sought to project that it made good buiness sense to develop and manufacture good diagnostic tools for TB.
The organisers must be lauded for the effort and the conference itself was an indicator of the commitment they displayed towards the control of TB. In what can be seen as a first, industry was included as a stakeholder in the dialogue itself. The scale and problem of TB was presented to them and what was also something of a first was that the government representatives present, admitted that diagnosis suffered owing to lack of robust diagnostic tools.
Some questions however remain in the minds of external stakeholders like me. What is more important? Numbers or lives? Understandably, industry must be aware of numbers, bottomlines, profitability, feasibility and any other words that fit into that category, as also to the fact that they have to answer their shareholders. But what about the people who suffer from undiagnosed or misdiagnosed TB? When these very priorities of industry prevent doctors from saving precious lives, who is answerable? There are giant pharma industries in the world that have made indeterminate amounts of money, developing and rolling out drugs for hypertension, diabetes, cancer and even TB. Can these companies not subsidise TB diagnostics? Can they not set aside minuscule amounts of their profits for the R&D of TB diagnostics? Or is that the altruistic view of a hopeless idealist?
The conference was hosted by St John’s Research Institute and McGill University, with technical assistance from Bill and Melinda Gates Foundation, Foundation for Innovative New Diagnostics, Stop TB Partnership and others.
Medical, public health and economic consequences of bad diagnostics: TB serodiagnostics as a case study
On 20 July 2011, the World Health Organization (WHO) published a policy recommendation against the use of currently available commercial blood (serological) antibody-detection tests to diagnose active tuberculosis (TB).
While serological tests work well for several infectious diseases (e.g., HIV, hepatitis B), existing serological tests for TB (both ELISA and rapid lateral flow tests) are not accurate or consistent enough to be useful. Even though many of these tests are manufactured in the developed world, none are approved for use by those countries’ regulatory authorities (e.g., FDA). A 2007 meta-analysis published in PLoS Medicine demonstrated that TB serological tests are not accurate, and an independent evaluation of 19 commercial rapid tests by TDR the following year confirmed those findings.
Unfortunately, the evidence from these studies was never translated into policy. While most regulatory bodies have mechanisms to withdraw or ban dangerous drugs and vaccines, there is little awareness about the consequences of bad diagnostics. Furthermore, there are few published data on the human and economic impact of inaccurate diagnostics, although common sense tells us that inaccurate tests lead to mismanagement, with adverse consequences for patients and health systems.
Another reason for the initial inaction on commercial serological TB tests 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. At $10-$30 per test, the cost of testing, plus the cost of TB drugs wasted on treating hundreds of thousands of patients with false-positive results, rival the entire Indian TB control program annual budget of $65 million. 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 at least 17 of 22 highest TB burden countries, from China to South Africa to Afghanistan. In all these countries, the tests are used only in the private medical sector. Weak regulation of diagnostics allows inappropriate tests to enter the market, where financial gains to doctors, laboratories, and diagnostic companies provide a strong incentive to keep such tests profitable. The losers in this economically-driven cycle are patients and public health.
In 2010, recognizing the importance of tackling this widespread problem, WHO convened an Expert Group to review the evidence and formulate a policy. The Expert Group considered an updated meta-analysis of test performance and a cost-effectiveness analysis. The meta-analysis, published in this week’s PLoS Medicine, synthesized evidence from 92 studies. The conclusion: commercial serological tests remain inconsistent and inaccurate, supported only by data of exceedingly low quality.
The cost-effectiveness study, also published in this week’s PLoS Medicine, 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. Where high-quality sputum microscopy is available, adding WHO-recommended automated liquid culture is cheaper and more effective than adding serology.
Based on the WHO Expert Group report and STAG-TB’s recommendation, the WHO released a first-of-its-kind “negative policy” on 20 July 2011, concluding that, since the “the harms/risks [of commercial serodiagnostic tests] far outweigh any potential benefits (strong recommendation)…these tests should not be used in individuals suspected of active pulmonary or extra-pulmonary TB, irrespective of their HIV status.”
It is important to clarify three points:
(1) The WHO policy actually encourages research to develop new serological tests for TB based on antigen/antibody biomarkers. The negative recommendation only involves existing commercial tests.
(2) The WHO policy does not include commercially available blood-based tests (interferon-gamma release assays) for latent TB infection. It only involves antibody-based (serological) tests for active TB.
(3) The WHO policy does not call for a ban on the technology platforms used for antibody or antigen detection (ELISA or rapid immunochromatography). They are excellent for many diseases, just not currently for TB.
The WHO policy against serological TB testing provides much-needed guidance at the global level. Now, it is up to high-burden countries to implement this policy by tightening regulations and educating doctors, laboratories and consumers to prevent continued abuse of such diagnostics.
India has already shown leadership in this area. Immediately following the WHO policy announcement, the Indian Revised National TB Control Program (RNTCP) issued an advisory against TB serological tests, and the National Laboratory Committee of the RNTCP endorsed the WHO policy recommendations. The challenge is now the Indian private sector, which manages nearly half of all TB cases in India. The private sector is strong in many other countries, including South Africa, Brazil, Indonesia, Philippines, Bangladesh, Kenya, Nigeria and Pakistan – all of these have serological tests on the market. The economic incentives that drive the private sector must be aligned with the health incentives of TB patients, which would push private doctors and laboratories to switch from serology to validated WHO-endorsed tests.
Lastly, intensive research is urgently needed to develop accurate and reliable point-of-care tests, offering more accurate and accessible diagnosis than is currently possible. This will require resources, scientific collaboration, industry engagement, and serious commitment from governments and donors.
This guest post is from Madhukar Pai, David W. Dowdy and Karen R Steingart, TB researchers at McGill University, Johns Hopkins Bloomberg School of Public Health, and University of Washington School of Public Health. Their studies in this week’s PLoS Medicine formed the basis for a historic first negative policy recommendation in the field of TB, from the World Health Organization, against inaccurate antibody-based serological tests for active tuberculosis.
None of the authors have any financial/industry conflicts to declare. All authors participated as observers (not involved in developing policy recommendations) in the WHO Expert Group meeting on TB serological tests held in July 2010. All 3 authors contributed to the cost-effectiveness analysis of serological tests in India. KRS and MP have contributed to previously published and updated meta-analyses on TB serological tests. KRS and MP are affiliated with the Stop TB Partnership’s New Diagnostics Working Group (NDWG). KRS serves as co-chair of the Evidence Synthesis& Policy subgroup of Stop TB Partnership’s New Diagnostics Working Group, while MP serves as Co-chair of the WorkingGroup. MP also serves as a consultant to the Bill & Melinda Gates Foundation (BMGF). NDWG and BMGF had no involvement in the two PLoS publications. MP serves on the editorial boards of PLoS Medicine and PLoS One.
Note: The views expressed in this article are the authors’ own and do not necessarily reflect those of NDWG or BMGF or WHO or JATB. This article was initially published as a guest blog on Speaking of Medicine on 9th August 2011.