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[This article was published in 2009 and updated in May 2012. Read the update here.]

When a new form of tuberculosis (TB) was raging through the shanty towns in the Northern Cone of Lima, Peru, Partners In Health (PIH) was on the ground trying to find a solution.

“Our group first encountered this in Peru in 1995, but science has known from the earliest days that you have to give multiple drugs to tuberculosis patients or resistance can develop very quickly, probably within the span of about a month or so,” says Salmaan Keshavjee, M.D., Ph.D., then an anthropologist. “As a phenomenon we saw drug-resistant TB in the 1950s and 60s, and there was a big outbreak of it in New York and Miami in 1991 and 1992,” adds Keshavjee, who has since become a physician and is now a senior TB specialist with PIH.

While as many as two billion people have been infected by TB, or one-third of the earth’s population, only about nine million people per year get active TB. The most vulnerable patients are immunocompromised or those suffering from malnutrition, and while patients can live for as long as 10 years with active TB, if left untreated, “It will kill you in the end,” says Keshavjee. “In the meantime, the TB bacillus is destroying part of your lungs and being transmitted to other people.”

The World Health Organization (WHO) estimates that 1.8 million people die every year from TB, making it essential that those with active TB receive treatment. Some patients may develop a drugresistant form of the disease; these strains require 18 to 24 months of treatment with numerous second-line anti-TB drugs, making treatment and compliance much more difficult. More than 70 percent of patients with the drug-resistant form of the disease can be cured, however the growth of drug-resistant TB is outpacing global efforts to fight it.

The multi-drug resistant form of TB, known as MDR-TB, strikes about half a million people each year, but is still susceptible to drugs, including capreomycin and cycloserine, two second-line therapies made by Eli Lilly and Company. And it is because of this experience that Lilly set out to create the Lilly MDR-TB Partnership, initially to fill the need for these drugs by supplying them at a concessionary price. The partnership also embarked on a transfer of technology program to generic manufacturers in high-burden countries, to enable them to produce the medicines locally. It has since evolved into an alliance of partners — private and public health care professionals, academics, patient- and community-advocacy groups, international organizations, and producers of medicines in developing regions — whose aim is to support the WHO goal in treating 1.6 million MDR-TB patients by 2015.

The Lilly MDR-TB Partnership consists of more than 20 global partners, including Partners In Health, the Centers for Disease Control, WHO, the Stop TB Partnership, the International Council of Nurses, the World Medical Association, the International Hospital Federation, the World Economic Forum, the International Federation of Red Cross and Red Crescent Societies, TB Alert, the Advocacy Partnership, the Global Business Coalition, the Global Health Advocates, Hisun Pharmaceutical, Shasun Chemicals and Drugs, SIA International/Biocom, Aspen Pharmacare, Purdue University, RESULTS, and Eli Lilly.

The partnership was created following the Peruvian crisis of the mid-1990s, according to Patrizia Carlevaro, head of Lilly’s International Aid Unit. “Doctors Without Borders asked me if Lilly could give them drugs for some former Soviet Union programs. We had these older drugs which were still very effective. I then began to think that we had to do much more than just give drugs and that’s when the inspiration for the partnership began.”

Lilly distributes the drugs at concessionary prices, but does so through an organization called the Green Light Committee which monitors MDR-TB projects throughout the world so that treatment protocols are correct and more drug-resistant strains don’t develop. “We asked the WHO and others to put together the Green Light Committee, to review requests for drugs in order to make sure that the programs were using the drugs correctly to avoid more drug resistance,” says Carlevaro.

“The Green Light Committee evaluates applications from countries. As a mechanism, the committee evaluates countries and approves them or not within two months,” says Keshavjee, who currently serves as the committee’s chair. If a country requires assistance to strengthen its program before being approved, the committee works with it through the process.”

The Green Light Committee (GLC) is comprised of representatives from institutions with specific programmatic, clinical, advocacy, scientific and managerial expertise [see sidebar at the end of story]. WHO is a permanent standing member. It is charged with reviewing applications, providing technical assistance to countries throughout the application and implementation processes, monitoring and evaluating GLC-approved programs to assess their progress and continued adherence to WHO guidelines, and assisting WHO with developing policy to control MDR-TB.

The Stop TB Partnership and WHO raise funds to sustain the work of the committee from national and government supported agencies, regional and international organizations, nongovernmental organizations, universities, research institutions and other sources. In addition, a cost-sharing mechanism helps support the efforts of the GLC initiative in countries receiving Global Fund grants for work on MDR-TB.

To become a quality-assured provider of TB drugs, drug companies have to go through the WHO prequalification program, a long process that can take two years or more. One of the key components of the Lilly partnership is transferring the technology to manufacture the two key drugs that can cure MDR-TB—capreomycin and cycloserine. Lilly identified four companies in the developing world and gave them the equipment, methodologies and training to produce these drugs as well as the manufacturing and marketing expertise to be able to provide the drugs to the growing number of countries, health ministries and donor agencies in need of these medicines for the TB pandemic. The four countries were those with the highest MDR-TB burden, so that drug supply could be available for the immediate needs of these nations as well as other countries hard hit by this deadly disease.

“The technology transfer was not a transfer of intellectual property per se, because the patent is over, since the drugs are more than 20 years old,” Carlevaro explains. “We give them all the technologies for manufacturing, and expert production technicians went to the local companies to teach them how to produce the two drugs,” she adds.

In addition to providing the transfer of technology, between 2000 and 2008 Lilly has supplied 2.3 million vials of capreomycin and 5.5 million capsules of cycloserine at concessionary prices to the WHO’s program. This has provided the much-needed drugs in the interim before the new companies were up and running.

An Emerging Economy Model

Of nine million cases of TB that occur annually, scientists now estimate that half a million are of the drug-resistant form. The Lilly partnership contributed to the GLC’s enrollment of around 56,000 patients to date, according to Carlevaro. While the disease is spreading faster than it is being treated, some countries like Russia, which have adopted the partnership model as a standard of care for treating the disease, have seen better progress than others.

“Russia has a very well-established health care delivery system, with sufficient physicians, nurses and resources, so our work is more focused on training those physicians,” says Amy Judd, director of program development in the division of Global Health Equity at Brigham and Women’s Hospital. With a grant by the Lilly Foundation, PIH subcontracts with Brigham and Women’s Hospital to administer the program.

“Whenever possible, we partner with local physicians and work through local ministries of health or the ministry of justice for the prison system, to educate physicians in drug-resistant TB diagnosis and treatment and advocate for effective care delivery models,” adds Judd, who notes that, while PIH is involved in other TB work, its partnership with Lilly is mostly limited to Russia.

Because Russia has established multi-drug resistant treatment as a national policy, the partnership may be improving treatment for as many as 25,000 patients per year, adds Judd. She also notes that the country sees 120,000 new cases of TB per year, of which 20 percent are multi-drug resistant.
“Partners In Health has doctors in Tomsk, Russia, but we’re not directly treating patients any more. Russian health care professionals basically run everything themselves, and since 2003 or 2004, we have been there just as consultants,” says Keshavjee.

Treatment is also more thorough in Russia than in some places, notes Keshavjee. “In our sites in Russia, patients start in the hospital and then are sent back to the community. With drug susceptible tuberculosis, patients become noninfectious in two weeks to one month, but for the drug-resistant forms, patients usually convert to a noninfectious stage in two months, so the patients are kept hospitalized for between four and six months,” notes Keshavjee.

Different Techniques Needed

Lilly also funds other partners to conduct extensive programs in Africa and Asia. Through grants to the International Council of Nurses, the World Medical Association and the International Hospital Federation, integrated TB training programs have been conducted for nurses, doctors and hospital administrators throughout Africa. “The problem with drug-resistant TB in Africa is especially critical,” says Lilly’s Carlevaro. “In Africa, 50 to 60 percent of the patients with HIV die from TB. If they’re not treated, they die very quickly, sometimes within a few weeks,” she explains.

Nonmedical measures are sometimes essential to effective implementation of the partnership, according to Carlevaro. “The Red Cross has more than 100 million volunteers globally, who go house to house, providing incentives such as a kilogram of sugar, for people who need treatment,” she says. “It seems strange because in the developed world, if you’re sick, you are usually willing to get treatment, especially if it’s free. In some parts of the world, however, if you’re sick, you can’t get to the treatment. In some cases if patients take the drugs for a few months, feel better, and then stop, they become re-infected. So, we try to make sure they complete their treatment.” While the course of treatment for regular active tuberculosis takes about six months, for the drugresistant kind it lasts up to two years,” says Carlevaro.

“The medicines can have a bad side effect profile, with almost universal nausea and vomiting. Patients sometimes don’t have families and social support, and they may lack nutrition, so the Red Cross delivers food assistance and helps patients take their medicines,” says Keshavjee.

Coordination Challenges

The Lilly MDR-TB Partnership is active in close to 80 countries across five continents, and virtually all partners agree that there have been logistical challenges in working in developing countries. When the Green Light Committee has to change its forecasts for drug purchases, the manufacturing partners must adapt their manufacturing schedules. On the other hand, the manufacturing partners also rely on WHO for its quality approvals, and slow response times and policy disagreements have sometimes frustrated partners and those waiting to receive the medicines. Some partners have had difficulty scheduling around grant disbursements and project evaluation requirements.

Prequalification procedures for drug quality and safety measures have taken more time for companies in developing countries to master. Thus, while the supply of drugs to the developing world has been able to meet demand to date, delays in getting one of the Lilly partner’s manufacturing facilities approved, have been addressed so that future supply lines will not be affected.

“What Lilly has done with their technology partnership is very innovative,” says Keshavjee, who lead-authored a white paper in November 2009 on barriers to solving the problem for the Institute of Medicine last fall entitled: “Stemming the Tide of Multidrug- Resistant Tuberculosis: Major Barriers to Addressing the Growing Epidemic.” MDR-TB is very concentrated in southern Africa, India, China and Russia, and Lilly has transferred its technology to companies in each of those regions.

Lilly’s technology transfer process has been very complicated. For example, the fermentation process required for capreomycin is a highly challenging and sophisticated process in any country. Hisun Pharmaceutical also had other challenges to address in safety and quality control, and Lilly had to provide support as part of the technology transfer.

In addition, there are sometimes problems with compliance by the manufacturers with the quality approval process in developing countries. “Some manufacturers don’t want to go through the WHO process because it takes too long,” says Judd. “So, some of the nonquality-approved products may not be good, or we have no way of knowing whether they’re good or not.” That is why the Lilly partnership has been critical to ensure that their partner manufacturers will go through either the prequalification process or approval by a stringent regulatory authority such as the U.S. Food and Drug Administration or the European Union. Lilly itself doesn’t need to go through the process because it is FDA-approved. As an important milestone in the Lilly MDR-TB Partnership, in June 2009, WHO added Lilly manufacturing partner Aspen Pharmacare’s cycloserine to its prequalified list.

Other problems of coordination also exist, Keshavjee adds. “We don’t know exactly how much medicine countries need,” he says. “Say they’re going to treat 2,000 patients next year but they don’t have the capacity or the labs, and they really end up treating 20 or 100. It’s very difficult to forecast what’s going to be done. It’s a problem with implementation within countries in some cases,” he says.

While coordination is a challenge, the partnership has succeeded in multiple spheres in its fight against MDR-TB. Through its multi-pronged approach, it has dramatically increased the supply of essential medicines and enabled manufacturers in high-burden countries to produce these drugs as well. However, the partnership realizes that drugs are not enough, and partner achievements have also been crucial in this battle.

By the Numbers 

• The International Council of Nurses has trained nurses worldwide in treating MDR-TB, with an estimated 16,000 nurses trained to date.
• Through programs led by PIH, more than 2,000 people have been trained on TB prevention, hospital management and clinical trainings in Russia and India alone.
• The International Federation of Red Cross held public awareness and antistigma campaigns that have reached more than 15,000 people in Kazakhstan, Romania, South Africa and Uzbekistan.
• Around 2,000 Red Cross Red Crescent staff volunteers have been trained in TB and MDR-TB, and nearly 1,000 community leaders received sensitization training.
• More than 300 clients with TB/MDR-TB signs are referred monthly to TB institutions, while more than 3,000 household visits have been conducted with MDR-TB prevention sessions.
• The International Hospital Federation has disseminated TB and MDR-TB control training manuals to aid hospital managers in more than 40,000 public and private hospitals and clinics in some 100 countries.

The impressive achievements of these partners augment Lilly’s effort in fighting MDR-TB by ensuring that the increased supply of MDR-TB drugs are put to proper use through consistent training of medical workers on an international scale. Furthermore, the awareness and advocacy work of the partners reduces stigma and increases awareness, which ultimately ensures that more people seek treatment for this illness.
By John Otrompke, J.D.

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Members of the Green Light Committee (as of September 2009)

Members are eligible for participation for a maximum of two years. An open call for membership is disseminated whenever a vacancy occurs, and members are usually drawn from the Stop TB Partnership Working Group on MDR-TB.

• Partners In Health — Current Chair
• U.S. Centers for Disease Control
• Hospital General de “Francisco J. Muniz”
• International Union Against Tuberculosis and
• Lung Disease
• KNCV (Dutch) Tuberculosis Foundation
• Médecins sans Frontières
• State Agency for TB & Lung Disease, Latvia
• World Care Council
• World Health Organization Standing Member