Making Antimalarial Agents Available in Africa
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《新英格兰医药杂志》
An infant in rural Africa has fever. Acetaminophen does not work. The fever spikes, and the father makes his way to the local kiosk and buys malaria medicine — chloroquine — that seems to help but then fails. A day later, the baby is dead.
The outcome has little to do with the curability of the disease and everything to do with economics — the economics of poverty and the economics of antimalarial drugs. It was this aspect of the malaria crisis that the U.S. Agency for International Development asked the Institute of Medicine to examine in 2001.1
The Africa Malaria Report 2003 prepared by UNICEF2 paints a grim portrait of the continent that bears most of malaria's burden at the beginning of the 21st century. Despite "intensified efforts to control the disease," the report states, "the number of children dying of malaria rose substantially in eastern and southern Africa during the first half of the past decade. . . . In West Africa . . . there was little change." No country in sub-Saharan Africa had a "substantial decline" in the disease. The culprit: the slow but imperturbable advance of chloroquine-resistant malaria across Africa. After decades of silently saving millions of lives, chloroquine — inexpensive, safe, and effective — is becoming impotent. One new class of antimalarial drugs, the artemisinins, could take its place.
The artemisinins are widely used in Asia, where resistance to chloroquine first emerged in the 1960s. After Chinese government scientists confirmed the antimalarial properties of compounds extracted from Artemisia annua (a plant known for centuries for its medicinal properties), companies in China and Vietnam began producing artemisinin-based drugs. But the African market did not develop, even when chloroquine's days were indisputably numbered.
Artemisia annua.
A major barrier was cost. At their cheapest, artemisinins cost at least 10 times as much as chloroquine. Cost was not the only factor, though. No global alarm had been sounded about the looming crisis because until the creation of the fledgling Roll Back Malaria Partnership at the end of the 1990s, the malaria-control community consisted of a cadre of scattered technical experts. Few heard the warnings of lone voices. In addition, the acknowledged failure of the market to produce drugs for "neglected" diseases meant that there was no trodden path for bringing the Asian production of artemisinins into the international drug arena. (That dynamic has since changed somewhat, with the creation of the Medicines for Malaria Venture, a partnership of public and private agencies for the development of new antimalarial drugs.)
To add to the complexity of the situation, by the late 1990s, the leading authorities on malaria had endorsed the concept of combination therapy as the new standard. The prime motivation was to preserve the effectiveness of the artemisinins and other still-effective antimalarial partner drugs in artemisinin-based combination therapies. As in the treatment of AIDS and tuberculosis, two effective drugs with different mechanisms of action can protect each other from the survival of resistant pathogens. Malaria knows no political boundaries, so for combination therapy to delay the emergence of resistance, it must be used in preference to artemisinin monotherapy as widely as possible. If monotherapies persist in some places, resistant strains will develop and spread globally.
The realities of how malaria is recognized and treated must be considered in the facilitation of widespread access to artemisinin-based combination therapies. There is general agreement (though little hard evidence) that in Africa, the majority of malaria treatments are purchased directly by patients or their surrogates and are used without input from the health care system. Improvement in the overall functioning of health care systems is an obvious long-term goal, but we cannot wait until such systems exist to supply artemisinin-based combination therapies while more and more children die of malaria. Either such therapies must be made available at an affordable price, through the same system that distributes chloroquine, or most people will not get effective treatment for malaria.
One artemisinin-based combination therapy, artemether–lumefantrine (Coartem, Novartis), is currently being produced and has a wholesale price of $2.40 per adult course (reportedly with little or no profit margin), as compared with 10 cents retail for chloroquine. Other formulations should enter the market soon, with an expected decline in price to less than $1 for an adult course. At the lower level, the global cost of the drugs in artemisinin-based combination therapies would be on the order of $500 million per year — barely noticeable in the budget of any major developed country. Nevertheless, this is an unmanageable cost for countries with per capita incomes of $2,000 per year or less. Subsidies are needed, but how can they best be applied?
There are few options. President George W. Bush, in his statement of June 30, has now made the treatment of malaria an official commitment of the United States. But if the U.S. initiative and others like it operate on a country-by-country basis instead of identifying a mechanism that would permit global subsidies and the global distribution of drugs, they will miss the opportunity to optimize both distribution and the useful lifespan of combination therapies.
It is hard to conceive that subsidizing artemisinin-based combination therapies at a local level — say, through vouchers — would be compatible with the current market-driven distribution system. It is not realistic to invent a new distribution system for antimalarial drugs, particularly when the existing one works reasonably well under the circumstances.
The solution is to allow subsidies to enter at a high international level — at the top of the distribution chain. This requires that the producers of artemisinin-based combination therapies sell directly to some international agency. Then the agency, in turn, can resell to distributors — governments and private wholesalers — at very low prices, the difference being the subsidy. The drugs would then flow down to the end users through the same pathways as chloroquine now does, with the requisite profit margins being taken where the private sector now operates. If these drugs start at a very low price when they enter the supply chain and if their supply is adequate, the price to consumers should be about the same as the current price of chloroquine. This is the heart of the recommendation of the Institute of Medicine.1
Centralized procurement from producers will have some important additional advantages. First, it will make it easier to enforce quality standards. Second, the procurement facility will guarantee the purchase of qualifying products for several years without waiting for orders from individual countries, providing an incentive for the drug manufacturers and the farmers who grow A. annua to enter the market. Currently, there is an artemisinin shortage. In this case, the long-run commitment is the solution to the short-term problem. Third, the proposed mechanism for the delivery of foreign aid — as a subsidy through the existing antimalarial-supply chains — is relatively undemanding of institutional capacity on the part of governments. In many of the poorest countries, the scarcest resource is not funding but, rather, the administrative capacity for procurement, financial management, and delivery logistics. This mechanism would bypass those potential bottlenecks.
As simple as the Institute of Medicine's concept appears to be, it requires management of a type that acts. The great need is fortitude on the part of leading development-aid organizations; they have to depart from standard operating procedures. The Institute of Medicine's recommendation has gained some currency as a centerpiece in the highest levels of discussions about the financing of malaria treatment (with more meetings planned), but no commitments have been made to adopt it.
The need for the general use of artemisinin-based combination therapies is by now universally accepted. The international community must recognize the need to finance and organize this use, through relatively uncomplicated steps and relatively modest expenditures.(Kenneth J. Arrow, Ph.D., )
The outcome has little to do with the curability of the disease and everything to do with economics — the economics of poverty and the economics of antimalarial drugs. It was this aspect of the malaria crisis that the U.S. Agency for International Development asked the Institute of Medicine to examine in 2001.1
The Africa Malaria Report 2003 prepared by UNICEF2 paints a grim portrait of the continent that bears most of malaria's burden at the beginning of the 21st century. Despite "intensified efforts to control the disease," the report states, "the number of children dying of malaria rose substantially in eastern and southern Africa during the first half of the past decade. . . . In West Africa . . . there was little change." No country in sub-Saharan Africa had a "substantial decline" in the disease. The culprit: the slow but imperturbable advance of chloroquine-resistant malaria across Africa. After decades of silently saving millions of lives, chloroquine — inexpensive, safe, and effective — is becoming impotent. One new class of antimalarial drugs, the artemisinins, could take its place.
The artemisinins are widely used in Asia, where resistance to chloroquine first emerged in the 1960s. After Chinese government scientists confirmed the antimalarial properties of compounds extracted from Artemisia annua (a plant known for centuries for its medicinal properties), companies in China and Vietnam began producing artemisinin-based drugs. But the African market did not develop, even when chloroquine's days were indisputably numbered.
Artemisia annua.
A major barrier was cost. At their cheapest, artemisinins cost at least 10 times as much as chloroquine. Cost was not the only factor, though. No global alarm had been sounded about the looming crisis because until the creation of the fledgling Roll Back Malaria Partnership at the end of the 1990s, the malaria-control community consisted of a cadre of scattered technical experts. Few heard the warnings of lone voices. In addition, the acknowledged failure of the market to produce drugs for "neglected" diseases meant that there was no trodden path for bringing the Asian production of artemisinins into the international drug arena. (That dynamic has since changed somewhat, with the creation of the Medicines for Malaria Venture, a partnership of public and private agencies for the development of new antimalarial drugs.)
To add to the complexity of the situation, by the late 1990s, the leading authorities on malaria had endorsed the concept of combination therapy as the new standard. The prime motivation was to preserve the effectiveness of the artemisinins and other still-effective antimalarial partner drugs in artemisinin-based combination therapies. As in the treatment of AIDS and tuberculosis, two effective drugs with different mechanisms of action can protect each other from the survival of resistant pathogens. Malaria knows no political boundaries, so for combination therapy to delay the emergence of resistance, it must be used in preference to artemisinin monotherapy as widely as possible. If monotherapies persist in some places, resistant strains will develop and spread globally.
The realities of how malaria is recognized and treated must be considered in the facilitation of widespread access to artemisinin-based combination therapies. There is general agreement (though little hard evidence) that in Africa, the majority of malaria treatments are purchased directly by patients or their surrogates and are used without input from the health care system. Improvement in the overall functioning of health care systems is an obvious long-term goal, but we cannot wait until such systems exist to supply artemisinin-based combination therapies while more and more children die of malaria. Either such therapies must be made available at an affordable price, through the same system that distributes chloroquine, or most people will not get effective treatment for malaria.
One artemisinin-based combination therapy, artemether–lumefantrine (Coartem, Novartis), is currently being produced and has a wholesale price of $2.40 per adult course (reportedly with little or no profit margin), as compared with 10 cents retail for chloroquine. Other formulations should enter the market soon, with an expected decline in price to less than $1 for an adult course. At the lower level, the global cost of the drugs in artemisinin-based combination therapies would be on the order of $500 million per year — barely noticeable in the budget of any major developed country. Nevertheless, this is an unmanageable cost for countries with per capita incomes of $2,000 per year or less. Subsidies are needed, but how can they best be applied?
There are few options. President George W. Bush, in his statement of June 30, has now made the treatment of malaria an official commitment of the United States. But if the U.S. initiative and others like it operate on a country-by-country basis instead of identifying a mechanism that would permit global subsidies and the global distribution of drugs, they will miss the opportunity to optimize both distribution and the useful lifespan of combination therapies.
It is hard to conceive that subsidizing artemisinin-based combination therapies at a local level — say, through vouchers — would be compatible with the current market-driven distribution system. It is not realistic to invent a new distribution system for antimalarial drugs, particularly when the existing one works reasonably well under the circumstances.
The solution is to allow subsidies to enter at a high international level — at the top of the distribution chain. This requires that the producers of artemisinin-based combination therapies sell directly to some international agency. Then the agency, in turn, can resell to distributors — governments and private wholesalers — at very low prices, the difference being the subsidy. The drugs would then flow down to the end users through the same pathways as chloroquine now does, with the requisite profit margins being taken where the private sector now operates. If these drugs start at a very low price when they enter the supply chain and if their supply is adequate, the price to consumers should be about the same as the current price of chloroquine. This is the heart of the recommendation of the Institute of Medicine.1
Centralized procurement from producers will have some important additional advantages. First, it will make it easier to enforce quality standards. Second, the procurement facility will guarantee the purchase of qualifying products for several years without waiting for orders from individual countries, providing an incentive for the drug manufacturers and the farmers who grow A. annua to enter the market. Currently, there is an artemisinin shortage. In this case, the long-run commitment is the solution to the short-term problem. Third, the proposed mechanism for the delivery of foreign aid — as a subsidy through the existing antimalarial-supply chains — is relatively undemanding of institutional capacity on the part of governments. In many of the poorest countries, the scarcest resource is not funding but, rather, the administrative capacity for procurement, financial management, and delivery logistics. This mechanism would bypass those potential bottlenecks.
As simple as the Institute of Medicine's concept appears to be, it requires management of a type that acts. The great need is fortitude on the part of leading development-aid organizations; they have to depart from standard operating procedures. The Institute of Medicine's recommendation has gained some currency as a centerpiece in the highest levels of discussions about the financing of malaria treatment (with more meetings planned), but no commitments have been made to adopt it.
The need for the general use of artemisinin-based combination therapies is by now universally accepted. The international community must recognize the need to finance and organize this use, through relatively uncomplicated steps and relatively modest expenditures.(Kenneth J. Arrow, Ph.D., )