BETHESDA, MD—Drug-resistant malaria strikes the hardest in countries with fragile economies and fractured healthcare infrastructures. Fighting the disease in these countries requires a complex solution, which includes the development of new drugs. But delivering drugs that work is only one part of the solution. According to Jean-Hervé Bradol, MD, past-president of Médecins Sans Frontières–France and current MSF research director, the solution to malaria in the developing world will need to take into account national politics, as well as social systems, and the sometimes-hindering regulations of humanitarian and health organizations.
Barriers in Fielding New Drugs
Bradol presented his experience working in refugee camps along the Thai-Burmese border in the early 90s as an example of the barriers inherent in treating malaria. “I arrived during the rainy season and malaria was running out of control in the camps,” Bradol said to a room of researchers at NIH last month. “We had outbreaks on many days, and my colleagues had already tried the common drugs—mefloquine and SPs (sulfadoxine pyrimethamine). We were trying all the drugs available at the time and still failing.”
All Bradol and his colleagues could do was document and publish accounts of the failure. Then patients began returning with stories of a drug they bought on the Chinese black market. These patients claimed that the Chinese drug was working, while the drugs provided by the Western humanitarians were failing.
Bradol managed to get his hands on a sample, which he discovered was artesunate, an artemisinin derivative. In combination with mefloquine it proved to be effective against malaria. “It was a major move,” Bradol said. “I won’t say it has solved most of our problems, but a large part of it.”
But there were considerable handicaps with using the drug at first. Artesunate was the outcome of a race between the Chinese and researchers at Walter Reed during the Vietnam War. The North Vietnamese had gone to their Chinese neighbors seeking a solution to malaria, which was ravaging both armies. While American researchers came up with mefloquine and SPs, the Chinese came up with artesunate.
That the drug came out of this competition was the first strike against it. The second was that it was not tested to international standards, and the third was that it was not patentable by western companies. “It is hard to move quickly with new kinds of drugs,” Bradol said. “WHO leadership used these arguments to not move too quickly.”
It was not until this past decade that large studies were done comparing artesunate with quinine, and it was not until 2007 that FDA approved an investigational new drug protocol for artesunate to be used as a severe malaria treatment in the US.
Scientific verification of a drug is only one requirement in fielding a new drug in a third-world setting. For a treatment to be accepted by WHO, reliable sources must be identified at reasonable prices; economic conditions must be created to finance the new protocol; legal questions about intellectual property must be addressed; authorizations from national authorities must be obtained for import and use; and new protocols must be written and staff trained.
“Most drugs,” Bradol said, “are not made for the type of patients we work with.”
From 1975 to 2004, tropical diseases and TB accounted for 12% of the global disease burden, but accounted for only 1.3% of new drugs developed during that span. According to Bradol, the research and development landscape has changed significantly, and the future is brighter. Non-profit organizations are helping create product development partnerships with pharmaceutical representatives, focusing on neglected tropical diseases, such as malaria.
But good intentions do not always result in good outcomes, Bradol said. “In my opinion, they need to be a bit more scrutinized in their outcomes. It’s a bit frightening to see that key public global health issues, like TB, [are] in the hands of private charitable institutions. One outcome of poor scrutiny in drug development and manufacturing efforts are drugs with a low percentage of the active ingredient. This can lead to an increase in drug resistance. We dedicate a lot of attention to studying slow drug clearance as a factor for resistance. These [weak drugs] can allow the parasite to build up a resistance to the active ingredient. That is one part of the work that is out of reach of doctors and scientists.”
Another aspect that, while in the physician’s area of expertise, is frequently out of his or her control, is the healthcare infrastructure in a third-world country. In tropical areas with hard rainy seasons, maintenance of clinic rooms and scientific equipment, especially microscopes used to diagnose malaria, can be difficult. “Never forget that these people are poorly paid, and poorly paid means poorly motivated,” Bradol said. “You need the simplest way of doing your work. Otherwise, the reasons for failing are too many.”
Asked about the rise of cell phone use and how telemedicine could improve chronic disease treatment in these areas, Bradol said that cell phones are a revolution and that they make it more convenient when the patient does not always have to physically be at the clinic. However, the worst handicap in these health systems is that they are not patient friendly.
“You cannot imagine how rude it seems to a patient in a consultation room or ward,” Bradol said. “And when you treat the chronic cases, not being patient friendly is not going to work at all. Of course, technological tools like cell phones will be something interesting. But what we need in a country where we’re working is a small cultural revolution among the health staff to learn how to be patient-friendly. The quality of relations between patient and doctor is based more on the doctor’s attitude.”