Public and Private Partnership Helps to Set the Standard of Care for Multi-Drug Resistant Tuberculosis -- UPDATE

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China , India , Republic of South Africa , Russia , Topic: Intervention/Prevention

[NOTE: This is an UPDATE to a case study initially published in 2009. Read the original case study for appropriate context.]

There are an estimated 500,000 new cases of multidrug-resistant tuberculosis (MDR-TB) each year.  The epidemic is driven by poorly managed treatment of drug-susceptible TB, exposure of patients to drug-resistant strains and the inadequate treatment of those who have contracted drug-resistant infections. Effective MDR-TB interventions require appropriate diagnostic capabilities, a steady supply of quality-assured second-line anti-tuberculosis drugs, and ways to monitor and treat patients over the two-year course of treatment.

To address the growth of this epidemic, the Eli Lilly & Co. Foundation launched The Lilly MDR-TB Partnership in 2003. The partnership sought to address all aspects of the crisis—from supporting appropriate intervention to improving access in middle- and low-income countries to two important second-line drugs manufactured by Eli Lilly, cycloserine and capreomycin. As part of its program, Lilly transferred the technology for the production of those drugs to seven companies in China, India, South Africa and Russia.That phase of the Lilly initiative was in its final stages in 2009, when the first volume of Global Health Case Studies reported on the Lilly partnership and a second partnership supporting MDR-TB interventions known as the Green Light Committee (GLC) Initiative.

Since then, Lilly has completed technology transfer for the production of both capreomycin (in 2011) and cycloserine (in 2007). In total, its Foundation has invested $135 million in advocacy, technology transfer and medical support since 2003. It has helped train 100,000 health care professionals and nurses in the appropriate diagnosis and treatment of MDR-TB and distributed guidelines and toolkits on effective intervention to more than 45,000 hospitals and clinics.   

In October, 2011, the Foundation announced that it would invest $30 million more over the next five years in the last phase of its program. In this phase, says Tracy Simms, Senior Advisor for Corporate Responsibility and Access at Eli Lilly, the Foundation will focus its efforts geographically—on India, China, Russia and South Africa—and thematically, on improving access to second line drugs and supporting health care provider training. “These are the high burden countries,” says Simms, “where the most significant impact of the disease is felt.” In fact, just China and India are thought to account for roughly 50 percent of all MDR-TB cases. “This allows us to better leverage our resources. We can go very deep—focused, but deep. We also feel that what we learn from these locations can be replicated at others, when we report our findings. That will really expand the value of what we are doing.”

The Foundation, he emphasizes, will work primarily as an enabler, collaborating closely with organizations that have an expertise in provider training, forecasting drug requirements and other issues central to improving the treatment and drug supply for MDR-TB. It has already engaged such entities as the Bill & Melinda Gates Foundation, Partners in Health/Harvard Medical School, the Stop TB Partnership, the Clinton Health Access Initiative and the World Health Organization. As the new phase gets underway, Simms expects the Foundation will continue working with these and other organizations.

Things have not gone quite so smoothly for the Green Light Committee, the main global mechanism for MDR-TB treatment access over the last 10 years. Established in 2000 as a multi-institutional partnership convened by the Stop TB Partnership and the WHO, the GLC sought to ensure access to quality-assured second-line drugs—including Lilly’s—at affordable prices for programs that met acceptable standards for the management and delivery of MDR-TB treatment. Quality assurance of drugs is as crucial to MDR-TB intervention as their appropriate administration: poorly manufactured drugs are thought to contribute to the expansion of drug resistance.

Programs in low and middle income countries that passed GLC muster could buy quality-assured drugs through the Global Drug Facility (GDF), the procurement arm of the Stop TB Partnership/WHO, at up to a tenth of the prices charged on the open market (based on prices in 2000). By tying program quality to the discounted quality-assured drug supply, the GLC hoped to reduce the risk that treatment of MDR-TB would generate even more resistant forms of the disease.

Programs that did not initially meet GLC standards received technical assistance from the Committee through the WHO and other technical partners. In 2002, The Global Fund to Fight AIDS, Tuberculosis and Malaria began requiring that all of its MDR-TB programs work through the GLC mechanism. By 2010, the GLC had aided programs in 80 countries and demonstrated that, with technical and material assistance, world class MDR-TB interventions could be effectively scaled up in the developing world.

In June 2010, however, the WHO informed partners in the GLC that its lawyers had reviewed the construction of the Committee and concluded that it would have to be disbanded—something that formally occurred a year later. “The idea of the GLC as a multi-stakeholder, institutional partnership turned out to be untenable,” says Salmaan Keshavjee, an associate professor at Harvard Medical School and senior MDR-TB specialist at Partners in Health who chaired the GLC between October 2007 and October, 2010. “The WHO argued that any WHO committee, and this included those that were committees of the Stop TB Partnership, had to be comprised of individuals, not organizations.

Their lawyers felt that the presence of institutional members—really, stakeholder organizations—was a conflict of interest rather than a strength.” This came as a surprise to Peter Cegielski, a Team Leader for Drug-Resistant Tuberculosis at the U.S. Centers for Disease Control and Prevention who also chaired the GLC between 2002 and 2006. “The WHO’s legal department,” he notes, “had reviewed the formation of the committee formally on two previous occasions, in 2002 and 2006, and both times found it to be appropriately constituted.”  Keshavjee attributes the WHO’s change of heart to its desire to exert more control over the committee, its funding and its activities. 

Asked about the change in opinion, the WHO Stop TB Department responded: “The dismantling of the GLC was the result of a major revision of the framework being used by WHO and partners to support countries in their response to MDR-TB. As a result, the terms of reference of the GLC were fully revised to be a ‘strategic committee at the global level with a dual role of advising WHO and partners,’ in order to play a role focused on support to countries rather than controlling the access to second-line anti-TB drugs. The new GLC, with the name ‘gGLC’, and its new terms of reference, had to reflect the 2010 WHO guidance on declaration of interests for bodies advising the WHO.”

But there were other substantive issues at play. Over the previous decade, projects approved through the mechanism had actually managed to treat just 23,000 patients, less than 0.5 percent of the estimated five million new MDR-TB cases in that period. As the global burden of MDR MDR-TB spiraled, the GLC mechanism couldn’t keep pace with the demand for its technical assistance.

“The GLC,” says Keshavjee, “was designed for pilot projects in 2000. It was never designed for scale up, never designed to be a system that could help countries deal with an estimated 500,000 new cases a year. The centralization of the mechanism at the WHO—from drug procurement at the GDF, which is housed at the WHO, to technical assistance provision, housed at the WHO’s Tuberculosis Department—really limited its capacity.” As a result, some countries were not able to receive the type of technical assistance that they required to scale up their capacity to treat MDR-TB.  For those that did receive approval, drug delivery times required patients to wait for extended periods (six to 18 months in some cases). 

Ultimately, says Cegielski, a perception took hold among treatment activists that the GLC was the primary obstacle to widespread drug access. “I must emphasize,” says Cegielski, “that the GLC did not restrict access to second-line drugs. The same market was there before the GLC as after. It was just a conduit for the highest quality drugs at the lowest prices.” The access issues, he says, arose primarily from underlying problems with the drug market, poor demand forecasting and many countries’ own requirements for drug importation and registration. Indeed, severe shortages persist even today. In any case, as Keshavjee points out, the GLC Committee itself could not remedy supply issues because it had outsourced procurement to the GDF, over which it had no control.

The gGLC established by the WHO and the MDR-TB Working Group of the Stop TB Partnership is comprised of individual experts that guide programs on how best to scale up MDR-TB treatment. It is in the process of establishing six regional GLCs (rGLCs), each convened and chaired by the TB coordinator in each regional WHO office to provide support to countries in their regions upon request. The GDF still acts as a procurement facility but countries go directly to it for second-line drugs, not through the new GLC committees. Nor is there any stakeholder representation on these expert committees. The hope is that with fewer countries under their purview, each of the rGLCs will be able to provide guidance as to the appropriate technical support required by countries for scale-up of MDR-TB treatment. 

But Keshavjee points out that no new mechanism for technical assistance delivery has yet been developed and many necessary changes have not been effected in rethinking the GLC. The WHO Stop TB Department responds that, “rather than creating new mechanisms for technical assistance, the new framework is focused in increasing efficiency in the supply and demand of support. The decentralization of activities to the regional GLCs is a central element in this framework.”

Still, Keshavjee and others suggest reforming the existing GLC rather than dismantling it would have been wiser. “We’d been advocating,” Keshavjee says, “for some way to deliver more relevant technical assistance, like the creation of regional centers of excellence to aid neighboring countries, or in-country implementation teams. None of that has materialized yet. We were looking for a wholesale change in the way the drug supply worked, for lower prices and timely delivery. That has not happened either. We’re left with more committees but no real mechanism to ensure a regular quality-assured drug supply and no real way to effect changes on the ground.” 

Asked about this, the GDF, Stop TB Partnership, responds that the market of second-line drugs is far more complex than almost any other drug. “In the last three years,” it notes, “the GDF and partners have made major progress in understanding the way market forces operate in the production, quality assurance, distribution and pricing of second-line drugs. Milestones achieved are reflected in a 37 percent increase in the value of second-line drugs procured through GDF from USD $57 million in 2010 to USD $78 million in 2011, and in a 50 percent increase in the number of patients enrolled on treatment for MDR-TB in 2010 compared to 2009.” It does acknowledge, however, that much work lies ahead to bring the numbers up meaningfully.

That, in fact, has been clear for some time. A WHO document describing the new GLC when it was launched noted that addressing the drug shortage will require strong political leadership and global stakeholder cooperation. That, in fact, is one thing that can safely be said of all aspects of the world’s response to MDR-TB. 

By Unmesh Kher

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