For almost a decade, Novartis has led a revolution in the treatment of malaria.

The main battleground is Africa, where malaria kills more than a million people every year, mainly pregnant women and children younger than five years of age.

When Novartis joined the fight against malaria during the late 1990s, Africa was on the brink of a public-health disaster. Malaria parasites had developed resistance to the older antimalarial drugs such as chloroquine on which African countries had relied for decades. In some countries, cure rates had dwindled as low as a single patient for every 10 patients treated. Physicians were desperate for an effective new medicine.

Working with partners in China, Novartis had developed Coartem, the first of a new class of antimalarial medicines known as artemisinin-based combination therapy, or ACT. Coartem included a component used for centuries in traditional Chinese medicine to treat fever. A second antimalarial compound, working through a different mechanism of action, acts synergistically, mopping up any parasites that might have survived the initial assault. Combining both components in a single pill, Coartem was the first ACT to offer the convenience of a fixed-dose formulation, enhancing patient compliance. In clinical trials, Coartem achieved cure rates of up to 95%, even in areas of multi-drug resistance.

To ensure broad access to Coartem, Novartis forged a partnership, with the World Health Organization to provide Coartem at no profit for use by public health systems in developing countries. In their agreement signed in 2001, Novartis and the WHO estimated that demand for Coartem might exceed 2 million treatments within five years.

The exceptional efficacy of Coartem, combined with availability of international donor financing through the Global Fund to Fight AIDS, Tuberculosis and Malaria, pushed demand for the new drug higher than anyone could have imagined. And as demand surged, Novartis and its partners responded with a rapid scale-up of production virtually unprecedented in the global pharmaceutical industry, particularly for a medicine supplied on a not-for-profit basis.

During 2006, more than 62 million treatment courses of Coartem were delivered to more than 30 countries across Africa, helping to save an estimated 200,000 lives. Production capacity for Coartem is even higher – 100 million treatments per annum – if orders are placed in a timely manner.

Manifold challenges

With some of the most populous countries in Africa now rolling out Coartem, malaria experts are upbeat about the potential impact for public health. “We have the opportunity to use Coartem as an entry point for making the whole government healthcare sector work better, not only by managing sick patients, but also by streamlining distribution and maintaining supplies of drugs to ensure effective treatment at remote healthcare facilities,” says Robert W. Snow, Professor of Tropical Public Health at the University of Oxford and one of the world’s leading authorities on malaria. “This could have a knock-on effect for all the diseases that are managed at local clinics and healthcare facilities,” Prof. Snow adds.

Robert W. Snow, Professor of Tropical Public Health, University of Oxford

At the same time, he cautions that problems “of actually implementing change have been manifold.” In Kenya, where Prof. Snow has lived for almost 20 years, the Ministry of Health changed national malaria-control policy and adopted Coartem as first-line therapy in April 2004. The first Coartem deliveries, however, didn’t reach thousands of healthcare facilities around the country until the end of last year.

Other countries have encountered similar problems, ranging from disruptions or delays in financing, to political commitment and buy-in from healthcare professionals. And surveys have shown that poor reporting and reordering by remote healthcare facilities, combined with weak transport systems, continue to result in stockouts in many countries where Coartem has been introduced.

Signs of Success
Novartis has helped to address these challenges by hosting a succession of Best-Practice-Sharing conferences for officials on the front lines in the battle against malaria. At the most recent conference, held in Kampala, Uganda, in late March, representatives from more than a dozen countries reported clear signs of progress along with frustrating glitches in distribution and drug management.

Data from KwaZulu-Natal province in South Africa indicated that dramatic declines in both the number of malaria cases and malaria-related deaths that followed introduction of Coartem and an integrated malaria-control program in 2000-2001 were maintained through 2005.

Separately, studies from two states in Nigeria showed that the rollout of Coartem increased the number of children younger than five seeking treatment at public health clinics. At the same time, there was a significant reduction in the number of children younger than five admitted to hospitals with severe malaria. “And we believe the reduction in admissions for severe malaria will invariably lead to a reduction in malaria mortality, and overall mortality among children under five,” says Henry Akpan, Director and Deputy National Coordinator, National Malaria Control Program in Nigeria.

In Zambia, the first country in Africa to adopt Coartem as first-line therapy against malaria, a survey of more than 100 health centers demonstrated substantial improvement in availability of the drug at remote healthcare facilities, as well as in the proportion of children who were treated with Coartem, compared to results of a similar national survey in 2004. Nevertheless, stockouts remain widespread at health facilities throughout Zambia; about 20% of children who seek care for a febrile illness leave clinics without receiving an antimalarial medicine, though Zambia’s guidelines recommend treatment of all childhood fevers with antimalarial drugs, irrespective of other causes.

Collection of data from the field measuring the impact of new malaria policies remains a major focus at the Best-Practice-Sharing conferences. “It is the yardstick by which you judge the whole drug-policy change,” says Prof. Snow, who served as co-chairman of the Kampala meeting. “Measuring results shows our governments that the new policies are making a difference. And it also shows donors that the money they are spending on us is actually having an impact.”

Combination of Interventions

From left: Dr. Henry Akpan, Director and Deputy National Coordinator, Nigeria’s National Malaria Control Program, and Dr. Anne Claire Marrast, Global Brand Medical Director from Novartis

Dr. Nduhura, Uganda’s Minister of State for Health, opened the Best-Practice-Sharing meeting in Kampala. He described how the spread of drug-resistant parasites increased the number of malaria cases in Uganda to more than 12 million in 2005, from 5.5 million cases in 1998.

“Coartem is highly effective against malaria parasites, eliminates the parasites and symptoms significantly faster and achieves higher cure rates than older drugs. And I want to take this opportunity to thank Novartis for reducing the price of Coartem, and also to thank the Global Fund for availing funds to procure Coartem,” he added.

“But there is a need for a combination of interventions, effective drugs like Coartem as well as vector control with indoor residual spraying and use of insecticide-treated bednets.”

Along with neighboring Tanzania and Ethiopia, Uganda is planning to resume indoor spraying of homes with DDT, widely acknowledged as the most effective insecticide against mosquitoes. “There has been a lot of debate and claims that countries using DDT won’t be able to export agricultural products to the European Union,” Dr. Nduhura mused.

“However the EU has made it very clear that as long as regulations of the Stockholm Convention of the WHO are followed, they have no problems with use of DDT for vector control. In Uganda, we don’t intend to depart from the convention and, all things remaining equal, we intend to start using DDT in areas for vector control by the end of June this year.”

Pediatric Formulation in Testing
In Kampala, Novartis scientists provided an update about development of a new dispersible formulation of Coartem, aimed to increase convenience of administration and improve palatability for young children. The new pediatric formulation is the latest in a succession of steps attempting to advance treatment of children. According to the WHO, more than 3 000 children in Africa die of malaria every day.

In recent years, Novartis and the WHO conducted ambitious clinical trials that paved the way to regulatory approval of Coartem in children with body weight of five kilograms, compared to the previous minimum weight limit of 10 kilograms.

The new dispersible formulation, a joint development project between Novartis and Medicines for Malaria Venture, has reached an advanced stage of clinical testing and, if submitted to regulatory authorities and approved, would represent another new milestone. Dispersing Coartem in milk or water for a child to drink promises to make dosing more reliable than the current practice of crushing adult tablets for use by children. And a new cherry flavor developed for the dispersible formulation masks the bitter taste that Coartem has in common with most other antimalarial medicines.

From left: Hon. Dr. Richard Nduhura, Uganda’s Minister of State for Health; Hans Rietveld, Marketing Director Malaria Initiatives Novartis, and Silvio Gabriel, Executive Vice President Malaria Initiatives, also from Novartis.

Strengthening the Supply Chain
Not surprisingly, the rollout of Coartem in large countries from Uganda to Tanzania and Ethiopia to Nigeria has exposed weak links in national supply chains. “Patients know Coartem is effective and can cure malaria in three days. Frequently they have already used the drug to treat a family member or themselves,” says Silvio Gabriel, Executive Vice President Malaria Initiatives at Novartis. “But too often, when they go to a clinic or health facility, no Coartem is available. So improving drug management must be a priority for countries. If Coartem doesn’t reach patients, it can’t cure them.”

For example, Nigeria and Tanzania have encountered problems in the front-end of the drug-management cycle: from forecasting and securing Global Fund grants to transferring funds within the country as well as between donors, the WHO and Novartis. In Nigeria, initial deliveries of Coartem were delayed by more than a year, squeezing deliveries and distribution originally planned for two years into a hectic, nine-month period. Despite promising results in some areas, the number of patients reached so far remains only a fraction of the original target.

Tanzania introduced use of artemisinin-based combination therapy on a small scale in 2003 and designated Coartem first-line therapy nationwide in 2004. But it took 16 months from disbursement of the initial installment of grant money from the Global Fund to Tanzania’s Ministry of Finance until Novartis completed delivery of the order in December 2006. “We saw very clearly in Tanzania that you can lose a lot of time just moving money around,” Mr. Gabriel said. Tanzania has become the first country to take advantage of a new procurement option involving direct payments to Novartis and also managing deliveries directly, without a professional procurement agency in an intermediary role.

Other countries are overhauling their logistics and distribution. Ethiopia, for example, has eliminated a spate of steps previously required to transfer Coartem and bednets from a central state-owned distributor to remote healthcare facilities. Of course, acknowledging early setbacks is a precondition for solving underlying problems; detailed analysis of forecasting, distribution and drug management will remain a key item on agendas of future Best-Practice-Sharing conferences.

“Novartis is proud to be part of this success story,” Mr. Gabriel says. “And these Best-Practice-Sharing workshops are another contribution to help make it happen. But the people on the front lines in these African countries are the pioneers. They are the heroes. And it is their achievement in this malaria story that will make its way to the history books.”