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ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At a current ex-manufacturer price of 1.35–2.40 US dollars (USD) per adult treatment course, ACTs are 20–40 times more expensive than conventional antimalarial medicines. The adoption by malaria-endemic countries of ACTs, which are 20-fold more expensive than conventional antimalarial medicines, has been made possible largely because of increased financial support provided by the Global Fund to fight AIDS, Tuberculosis, and Malaria (GFATM). Newer initiatives to support malaria control such as the US President’s Malaria Initiative (PMI) and the World Bank Booster Program, which were launched in 2005, are additional sources of support for this change, but until now, their financial disbursements have been considerably less than those of the GFATM. These initiatives, will, collectively, contribute no more than one quarter of the global resource requirements for ACTs estimated at 500–600 million treatment courses per year.4 Nor are these external financial mechanisms likely constitute sustainable and predictable sources of financing in the long term, given that they themselves are subject to fluctuations in donor commitment. Lately, international attention is being focused on more innovative financing schemes. In particular, those that would generate more stable, predictable revenue with which to fund programs that require recurrent funding such as for the procurement of life-saving antimalarial medicines. A core group of countries is supporting a new initiative, the International Drug Purchasing Facility (IDPF/UNITAID), based on an "airline tax" to mobilize resources for the procurement of medicines and diagnostics for tuberculosis, HIV, and malaria. This initiative aims to influence market dynamics to lower drug prices and increase supply; it will also explore a global subsidy for ACTs5,6 to reduce ex-manufacturer price in both the public and private sectors. An international subsidy to promote the universal adoption of ACTs and discourage monotherapies will have both a humanitarian scope of saving lives and the economic rationale of protecting a public good, which artemisinin derivatives are.5
In anticipation of these prospects for increasing access to ACTs, we analyzed the global situation with respect to the use of these new malaria treatments. We describe the process of ACT policy adoption and implementation in countries and the interplay between global product availability, demand, and pricing. We also examined the challenges, including the threat posed by the extensive availability of artemisinin monotherapies in the private sector, and their continued use by malaria patients.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Since 2000, an increasing number of endemic countries, numbering 67 at present, have adopted ACTs in the treatment of uncomplicated falciparum malaria (Figure 1
). With a time-lag of 12–18 months between policy adoption and implementation, the proportion of countries actually deploying ACTs in the general health services has also increased. Initially, most of these countries began by limiting the deployment of ACTs to either selected geographical areas (e.g., districts or provinces supported by grants or donors), to the most vulnerable population groups (e.g. children younger than 5 years of age), and/or to certain levels of the health care system (e.g., where microscopy is available). With the exception of Cambodia, ACTs have not yet been introduced beyond health facilities into home-based management programs.
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. Most countries (65 of 67), including 41 in Africa, adopted ACTs as their first-line treatment of uncomplicated falciparum malaria. Only two countries adopted ACTs exclusively as second-line treatment. There are nine more endemic countries with recorded treatment failure rates of their first-line medicines exceeding 10%,7 which, according to WHO guidelines,8 should adopt ACTs (Botswana, China, Colombia, Eritrea, Nepal, Pakistan, Sri Lanka, Swaziland, Vanuatu).
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A majority of countries have adopted a single ACT, but a few adopted different ACTs for different geographical areas of the country (e.g., Peru, South Africa, Sudan, and Tanzania). Some countries (Nigeria and Uganda) have formally adopted two ACTs as first-line treatment, although only one is procured by the government.
Global supply and demand for ACTs.
The number of ACT treatment courses procured by national governments of endemic countries for use in their public sector increased from around half a million in 2001 to 31.3 million in 2005 (Figure 1
)—25.5 million of these being for countries in Africa. More than 80% of these orders were placed through WHO. From January 2005 to July 2006, the total ACT procurements for the public sector made by WHO, UNICEF, and to a lesser extent, by Crown Agents has been 62.6 million treatment courses: 80.8% of these orders were for artemether/lumefantrine, 12.5% were for artesunate plus amodiaquine, and 6.7% were for artesunate plus sulfadoxine/pyrimethamine.
At the time when the ACT market was quite new and unstable, two key interventions helped to prevent ACT prices from escalating: a differential pricing agreement between WHO and Novartis Pharma AG, the manufacturer of artemether/lumefantrine (at that time a single-source product) to supply the medicine at cost price for public sector use in endemic developing countries and the joint call by UNICEF and WHO for annual tenders for multi-source generic ACTs (artesunate plus amodiaquine, artesunate plus sulfadoxine/pyrimethamine, and artesunate plus mefloquine) meeting minimum quality standards. The latter not only increased market competition among ACT manufacturers but also led to quality ACTs entering the market. It also contributed significantly to reducing the price of artesunate + amodiaquine from USD 2.60 in 2003 (ex-factory price of adult treatment course with the two compounds in separate blister packs) to USD 1.68 in 2004 (for the co-blistered product), and even further, to the current price range of 1.35–1.55 (Table 2).
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In 2004, the rapid increase in demand led to a global shortage of the single-source ACT, artemether-lumefantrine, manufactured by Novartis Pharma AG. The public sector demand for artemether/lumefantrine increased rapidly from 2001/2002, when WHO ordered only 0.32 million treatment courses, to 2004/2005. During the period from October 2004 to March 2005, WHO and UNICEF ordered a total of 4.5 million treatment courses of treatment, but the company had artemisinin supplies to produce only 2.4 million treatment courses. The reason for the shortage was an insufficient supply of artemisinin, the raw material extracted from the plant Artemisia annua, needed to manufacture artemether. Cultivation of A. annua requires a minimum period of 6 months, and extraction, processing, and manufacturing of the final product requires an additional 3–5 months. The surge in the global demand for artemisinin created a temporary market crisis, with a consequent global shortage of artemether-lumefantrine that lasted until the end of 2005. Since then, the manufacturing company has invested in sourcing stocks of artemisinin raw materials and has expanded its manufacturing facilities to increase production capacity to meet the global demand. The cultivation of A. annua and the extraction of artemisinin raw material, which, until recently were restricted to a few countries—notably Vietnam and China, has now been extended to several countries, including in Africa. The multi-source ACTs that are manufactured by several companies were never subject to shortages.
The production capacity for ACTs in 2006 by the five major pharmaceutical producers listed in Table 2, estimated at 130 million treatment courses, exceeds the public sector demand for ACTs, which are currently estimated at 90 million treatments for 2006. The global forecast for 2007 and 2008 for the public sector requirements of ACTs, taking into account existing financing mechanisms and deployment rates in countries, is in the order of 160 and 200 million treatment courses, respectively.
Malaria treatment practices in the private sector and the threat posed by monotherapy. Studies on treatment seeking behavior of people have highlighted the importance of both the formal and informal private sectors as sources of malaria treatment.9–13 They also point to problems in the quality of health care10,14,15 and those relating to the heterogeneous quality of medicines available in the market.16 A wide variety of antimalarial medicines is available in the retail sector of malaria-endemic countries, in sharp contrast to the limited product range deployed by the public sector. In 2002, a study in Kenya identified 218 different brands of antimalarials registered in the country, including 12 different brands of artemisinin monotherapies.17 Given the unruly nature of the market, it will be important to monitor and analyze on a continuous basis the quality and price of medicines available and to scrutinize the distribution systems of antimalarial medicines in both the formal and informal private sectors.
The lucrative nature of the pharmaceutical market and the opportunities offered by the rapidly increasing demand for antimalarial medicines make them a high value commodity in the private sector—in particular, the artemisinin derivatives, because of the rapid clinical cure they produce, are prone to exploitation. The rapid expansion of artemisinin products marketed mostly as monotherapies is one of the most striking changes seen recently in the private sector of malaria-endemic countries.
Today, > 40 pharmaceutical companies manufacture artemisinin monotherapies as finished products and are marketing > 60 brands of these products in endemic countries, generally at prices lower than those of ACTs. With one exception (Sanofi-Aventis), they are all generic manufacturers from Africa (Cameroon, Ghana, Kenya, and Tanzania), Asia (China, Malaysia, India, and Vietnam), and Europe (Belgium, Cyprus, Denmark, Germany, Greece, Italy, Netherlands, and Switzerland). Most companies manufacturing artemisinin products are based in India, China, and Vietnam.
Given the diverse and exploitative nature of the market, a major responsibility for maintaining the quality of medicines falls on regulatory authorities in countries. A total of nine countries with resistant P. falciparum malaria (Afghanistan, Brazil, Eritrea, Ethiopia, Iran, Malaysia, Philippines, Saudi Arabia, and South Africa) have never registered oral artemisinin monotherapies. Thailand registered oral artesunate in 1994, with a restriction on distribution regulated by the Ministry of Health, which resulted in very limited use of the product (i.e., as third-line treatment when quinine + tetracycline treatment failed). One country, Sudan, has withdrawn the marketing authorization for artemisinin monotherapies after it began implementing an ACT-based treatment policy.
In January 2006, WHO made a strong appeal to pharmaceutical companies, National Drug Regulatory Authorities, and international funding and procurement agencies to manufacture, procure, and promote ACTs as the best standard of care for malaria treatment. It called for an end to the deployment of artemisinin monotherapies for the treatment of uncomplicated malaria—a practice especially common in the private sector—to prevent the development of resistance to artemisinins. As a result, 17 of 40 pharmaceutical companies made public commitments to support the WHO position and to stop marketing artemisinin monotherapies within a short span of time and increase the production and marketing of ACTs in both public and private sectors.
National health authorities of Benin, Comoros, and Gabon have taken formal steps to withdraw marketing authorizations for artemisinin monotherapies in their respective countries. Recently, India, Kenya, and 11 others in Southern Africa belonging to the Southern African Development Community (Angola, Botswana, Democratic Republic of Congo, Madagascar, Malawi, Mozambique, Namibia, Swaziland, United Republic of Tanzania, Zambia, and Zimbabwe) have made a formal commitment to withdraw marketing authorization for artemisinin emanotherapies. In May 2006, with the launch of its new ACT-based treatment policy, the Ministry of Health of Cameroon withdrew marketing authorization for 42 antimalarial medicines. They included 25 different brands/formulations of artemisinin monotherapies, 11 of amodiaquine, 3 of halofantrine, and 1 brand each of pyrimethamine, proguanil, and Peschiara Fuchsiaefolia (Malarex). Forty-seven countries have yet to withdraw their marketing authorization for oral artemisinin monotherapies.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At present, all but 9 of the 76 malaria-endemic countries that should have adopted ACTs on the basis of the levels of resistance to previous antimalarials have done so, and others are likely to follow. This process has been greatly facilitated by increased global resources made available for malaria control such as through the GFATM, and now reinforced by other more recent initiatives such as the PMI and the World Bank Booster Program. However, because of the inherent instability of external funding, many high burden countries continue to remain at risk of their ACT supplies being interrupted. The provision of such essential health interventions as access to life-saving medicines ought to be underpinned by more stable financing mechanisms if the burden of these diseases of poverty are to be alleviated. Despite many countries having adopted ACTs at the current levels of deployment, only a fraction, probably < 10% of their malaria patients, are able to access these medicines, especially in high burden countries in Africa.
Financial barriers are not the only impediments to accessing ACTs. This experience has shown that the infrastructure and capacity for drug supply management in countries needs to be strengthened much further if these medicines are to be delivered effectively. ACTs pose specific logistics challenges not associated with conventional antimalarials: the four different ACTs currently recommended by WHO are each available in three to four age-specific course-of-therapy blister packs with a short shelf life of 2 years. This demands greater accuracy in quantifying drug requirements and greater skill in managing supplies. In the transition to ACTs, countries were also faced with having to change the behavior of health personnel and consumers for the appropriate use of the new medicines. Furthermore, the high price of ACTs calls for targeting them to malaria patients rather than using them to treat all fevers. However, the parasitologic confirmation of malaria by either microscopy or rapid diagnostic tests (RDTs) is still hampered by weak quality control systems, especially in peripheral settings; the requirements for a cool-chain distribution system for RDTs; and difficulties in changing prevailing practices of treating fevers as malaria regardless of parasitologic test results.
Two major challenges remain. One is that access to ACTs remains limited in rural communities that bear the greatest burden of disease and will continue to be so unless these medicines are deployed in home-based management programs. For this to happen, reliable drug supply systems must link peripheral health services with sustainable community-based distribution systems.18 The second is that penetration of the private sector by quality and affordable ACTs has not yet been achieved; a pilot project in Cambodia has met with limited success. This is likely to require new approaches such as introducing a global subsidy for ACTs.
Over a relatively short span of 4 years, the global ACT market has grown into a thriving industry supported by both research and development–based and generic pharmaceutical companies, market forces having rapidly permeated down to the suppliers of raw material and agricultural growers. Key to this achievement was the assurance of financial purchasing capacity for ACTs offered by external financing mechanisms, in particular, the GFATM, and several market-priming interventions made by the international community. The nature of the ACT market, particularly in its current phase of expansion, is, however, vulnerable because of the dependence of manufacturers on a raw material that requires long cycles of agricultural production and of the dominant public sector market, which depends largely on erratic overseas development assistance.
Despite greater product availability, the current prices of ACTs remain too high. Increased global financing and pooled procurement mechanisms will lead to large orders of quality products and to economies of scale. With increased competition in a large and secure market, wholesale prices for a course of ACT (currently US$ 1.50–2.40 ex-factory public sector price per adult treatment course) could fall to USD 1.00 within 2 years. Developers of the next generation of fixed-dose combination ACTs, which are in the pipeline, also aim to keep within this price range for the public sector. Any further reduction in the price of ACTs is not, however, likely to emerge through market forces, but could result from breakthroughs in biotechnology or chemical synthesis of artemisinin analogs.
The quality of ACTs is a major concern in this transition, with most manufacturers of ACTs having limited experience in meeting stringent quality requirements. Although most still fail to meet WHO prequalification standards, there is good progress being made in manufacturers achieving compliance with Good Manufacturing Practices and other quality standards set by WHO’s and UNICEF’s procurement services.
These global quality control mechanisms have helped greatly to ensure the procurement of high-quality medicines in the public sector, but the private sector is widely open to exploitation by manufacturers of ACTs of heterogeneous quality and of artemisinin monotherapies. The artemisinin derivatives, in view of their high value and demand, have been the target of counterfeiters. Initially detected in Southeast Asia,19 counterfeit artemisinin derivatives were later documented in Africa,20 where the high malaria burden, poor patient information, limited quality control capacity, and large unregulated private sector create a favorable environment for artemisinin counterfeits.
The use of monotherapy on a large scale, as is happening now in the private sector, will promote resistance to artemisinins, as has been the case with all previous antimalarial medicines. The withdrawal of monotherapy from the market and promotion of ACT use is a major challenge that will require a much stronger medicine regulatory system in countries. Making ACTs significantly less expensive than current mono-therapies in both the public and private sectors such as through a global subsidy may also help to achieve this objective. Such interventions should receive the highest consideration, given that, as of now, there are no other medicines against malaria for large scale deployment with an efficacy comparable to that of ACTs.
Received October 25, 2006. Accepted for publication November 7, 2006.
Acknowledgments: The authors thank Drs. Arata Kochi, Maryse Dugue, Peter Olumese, Pascal Ringwald, Wilson Were, and Sergio Spinaci, Francoise Mas, and Elise Pacquetet for ideas, helpful dialogue, and sharing information.
* Address correspondence to Andrea Bosman, Global Malaria Programme, World Health Organization, Av. Appia 20, 1211 Geneva, Switzerland. E-mail: bosmana{at}who.int 
Authors’ addresses: Andrea Bosman, Global Malaria Programme, World Health Organization, Av. Appia 20, 1211 Geneva, Switzerland, Telephone.: 41-22-791-3860, Fax: 41-22-791-4824. Kamini N. Mendis, Global Malaria Programme, World Health Organization, Av. Appia 20, 1211 Geneva, Switzerland, Telephone: 41-22-791-3751, Fax: 41-22-791-4824.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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  J. G. Breman, M. S. Alilio, and N. J. White Defining and Defeating the Intolerable Burden of Malaria III. Progress and Perspectives Am J Trop Med Hyg, December 1, 2007; 77(6_Suppl): vi - xi. [Full Text] [PDF]
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