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The debate goes on over China's ongoing production of malaria monotherapy, which is thought to promote drug resistance. Jane Wu reports.

It is a godsend for half a billion malaria patients in Africa, tens of thousands of farmers in Asian countries and a range of drug companies. But the unique medical and commercial value of the herbal extract artemisinin have made it a contentious issue in China.

Artemisinin, considered the most efficient treatment for malaria, is the source of a stand-off between the World Health Organization (WHO), Chinese drug companies and the Chinese government.


In March the Wall Street Journal reported that the WHO was urging the Chinese drug company Kunming Pharmaceutical Corp. to stop producing its artemisinin monotherapy. Using artemisinin alone is thought to trigger resistance to the herb's action in malaria parasites.

According to the journal, Kunming says that the WHO lacks evidence for the mechanism of resistance and is simply trying to remove Chinese companies from the artemisinin market.

Last week (26 April) the WHO and Kunming officials met in Geneva for face-to-face negotiations. By the second day, news came that a 'positive' result had been reached.

According to Andrea Bosman, medical officer with the WHO's global malaria programme, Kunming has agreed to stop producing or selling oral artemisinin-based monotherapies by the end of this year.

"By October, they will stop producing or selling capsule or tablet monotherapies," Bosman told SciDev.Net.

Kunming has yet to make an official comment. But if a compromise has been reached it could be the first step to resolving a long-standing dispute.

Chinese origins

The Chinese have used artemisinin, derived from the herb Qinghao, for thousands of years.

In the 1970s hundreds of Chinese scientists researched ways of isolating the compound in order to protect Chinese soldiers from malaria during the Vietnam war. They successfully developed the drug, but due to a lack of patent law at the time, failed to establish a patent for it.

Then in 1990, in an effort to combat spreading resistance to the drug, the WHO recommended that artemisinin be used only in combination with other anti-malarials.

Chinese scientists have subsequently developed an artemisinin-based combination therapy (ACT) called Coartem. This remains the only fixed-dose combination therapy for malaria approved by the WHO.

Credit: Scott Bauer/
US Agricultural Research Service

Swiss drug firm Novartis acquired the rights to market the therapy outside China in 1994. Chinese companies continue to supply the raw material for the drug to Novartis, and China continues to hold a domestic patent for the therapy.

But Chinese companies still produce artemisinin monotherapies alongside ACTs to meet the huge demand for cheap monotherapies in the developing world.

An official with the Ministry of Commerce, who asked to remain anonymous, said China currently controls about a third of the global market in artemisinin monotherapies. The rest is shared by African and Asian countries using Chinese production methods.

Kunming sold about US$5 million worth of its monotherapy in 2004, according to Yu Zelin, general director of international trade at Kunming.

The Chinese authorities back the sale of monotherapies, saying that the WHO must allow them to exist alongside ACTs for a longer period of time.

"Monotherapy is still in great demand," says Yang, a government official in the malaria programme, who asked to be referred to only by his surname. And that demand is not only fuelled by the desire for financial gain: for many, worries about resistance are unfounded.

Antimalarials and resistance

"Generally speaking, combination therapy is more effective than single therapy. But any drug which has been frequently used will contribute to resistance," Zhu Dayuan, the Shanghai-based scientist who invented Coartem, told SciDev.Net.

Zhu says there is "no scientific proof that combination therapies will have less possibility of incurring resistance" than monotherapies.

But a number of published studies report on how malaria monotherapies can result in resistance.

In 2005, The Lancet published research from an international team that found emerging resistance to artemisinin in West Africa.

Lead researcher Ronan Jambou, of the Pasteur Institute, Senegal, says that lowered sensitivity to artemisinin in the malaria parasite was related to mutations in a gene called serca, which is known to be sensitive to this class of compound.

The same study found no resistance in parasites in Cambodia, which was only using artemisinin in combination with other therapies athe time of the study. This led Jambou and colleagues to believe that the parasite is less likely to develop resistance to combined therapies than to a drug used in isolation.

There is a huge demand for
monotherapies in the
developing world
Credit: WHO / TDR / Crump

However, Yan Xiaohua, vice president of Shanghai Fosun Pharmaceutical, told SciDev.Net that a few cases of resistance cannot produce a general rule.

"We support the WHO's resolution on combined therapies," Yan said. "But monotherapies also have advantages that the WHO should not ignore."

Monotherapies are less toxic than ACTs, making them vital for vulnerable groups such as pregnant women or babies, said Yan. He added that the WHO still purchases thousands of doses of artemisinin-based monotherapies for such groups.

Last year, the WHO told 18 pharmaceutical companies around the world to stop marketing artemisinin monotherapies, again citing the need to combat resistance to the compound.

While the Chinese Ministry of Health agrees with the WHO that combination therapy is necessary for optimal treatment of malaria, it points out that it is the misuse of drugs ― not proper use under prescription ― that often leads to the development of resistance.

Chinese companies, including Kunming, are unhappy with the WHO's decision. Some dispute the WHO's emphasis on artemisin resistance. Others argue that artemisinin-based drugs are the inventions of Chinese scientists and that the WHO is denying them a share in the market.

And there are further suggestions that the WHO's decision favours Novartis, which some claim has made a huge profit out of the Coartem ACT.

Coartem: profitable or not?

Novartis insists that it sells Coartem at cost price and has made no profits out of it.

"They [Chinese monotherapy producers] may think Novartis has made a lot of money out of Coartem, but our company does not think so," says Liu Tianwei of the China International Trust and Investment Corporation (CITIC) Group, who represent Novartis in their Coartem licensing deals .

Liu says Novartis produced 33 million doses of Coartem in 2005, nine million of which were sold to the WHO. In 2006 it sold 62 million doses to the WHO, with a sales value of about US$170 million. This year's sales should equal that.

To date, Novartis has invested about US$100 million to expand sales of Coartem, according to Liu.

In 2001 the company reached an agreement with the WHO to sell Coartem at a price of US$2.4 per dose.

"If Novartis wanted to make big profits it should have sold Coartem in private markets, where the price per dose can be US$10," he said.

He added that over the years, the deal has brought profits of approximately 50 million yuan (US$6.5 million) to Chinese companies that supply raw materials to Novartis ― including Kunming.

But the Chinese Ministry of Health has other views.

"Novartis has made huge profits. It sells the drug at a higher price than its cost price," says Yang.

He added that the Swiss company has made about US$100 million from Coartem this year.

From mono to combination

The Ministry of Health has also cast doubt on the WHO's standards for drug approval, as it has been several years since it approved any combination therapy apart from Coartem.

"China is so far simply a supplier of raw materials, though we have actually developed several new and effective combination therapies," says Yang, adding that the WHO guidelines for malaria treatment need to be updated to allow for new therapies.

Kunming, for example, has developed is own ACT called Acro, which, according to the Wall Street Journal, WHO officials recognise as a promising drug.

At the showdown meeting with Kunming last week, the WHO encouraged the company to submit related materials about Acro so that the organisation could begin to review the new medicine.

"The company has agreed to make every information about the new medicine available to the WHO," Bosman told SciDev.Net.

He added that Kunming also asked advice about the methods used in the WHO's review of ACTs. Acro still needs further research before it can be approved.

However, Ma Weipeng, a senior member of Kunming's research and development division, told SciDev.Net that WHO approval is not necessary for the company to sell Acro abroad.

"We can register a qualification certificate individually in local drug administrations to boost our sales," said Ma.

Strangely, the success of Acro may end up aiding the WHO's quest to stop monotherapy production.

The future of artemisinin

While Kunming is negotiating with the WHO, other Chinese artemisinin manufacturers are quietly developing new ACTs and artemisinin-based treatments for diseases other than malaria.

Shanghai Fosun Pharmaceutical is joining forces with scientists in the Chinese Academy of Sciences to develop a new anticancer drug based on artemisinin.

"We will begin clinical tests shortly, and we believe it will be a very promising drug on the market," said Li Ying, a researcher with Shanghai Institute of Materia Medica under the Chinese Academy of Sciences.

Whatever the outcome of the WHO's negotiations, artemisinin will, it seems, be staying in the pharmaceutical arena for a long time to come, and in ever-changing guises.