WHO/HTM/GMP/2014.3

Emergence and spread of artemisinin resistance calls for

intensified efforts to withdraw

oral artemisinin-based monotherapy from the market

1 May 2014

Key messages

In January 2014, the WHO Global Malaria Programme published the latest status report on artemisinin resistance: foci of artemisinin resistance have been identified in five countries in the Greater Mekong subregion, and resistance is suspected in two countries and one territory in South America.

Continued use of oral artemisinin-based monotherapy (oAMT) is widely considered to be one of the main contributing factors to the development and spread of resistance to artemisinin and its derivatives.

In May 2007, all Member States endorsed a World Health Assembly resolution that urges Member States to cease the marketing and use of oAMT1 in both the public and private sectors, and to promote the use of artemisinin-based combination therapy (ACT). Despite comprehensive regulatory action and substantial progress, oAMT is still available in many countries, as discussed in the text.

In view of the latest evidence on artemisinin resistance, intensified action is required to protect the therapeutic life of ACT, which is the mainstay of treatment for malaria caused by Plasmodium falciparum. No alternative medicine is ready to enter the mar-ket in the next few years to replace ACT.

The loss of artemisinin derivatives would have devastating consequences on people’s health in malaria-endemic countries and threaten the recent progress in malaria control achieved in many countries.

1. This recommendation refers only to oral artemisinin-based monotherapy. Rectal and injectable formulations (e.g. artesunate

suppositories and artesunate injectables) are still required for pre-referral treatment and for the treatment of severe malaria, respectively (1). Moreover, in exceptional cases, the manufacture and export of oAMT might still be necessary for co-packaging with a partner medicine in artemisinin-based combination therapy (ACT) products that are not yet available as fixed-dose combinations.

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Table of contents

Artemisinin-based monotherapy and risk for drug resistance of Plasmodium falciparum .................. 3

Latest evidence on artemisinin resistance ............................................................................................ 4

Drug pressure and its impact on resistance to antimalarial medicines ................................................ 4

WHO recommendations on phasing out oral artemisinin-based monotherapy .................................. 5

Monitoring enforcement of regulatory action on artemisinin-based monotherapy............................ 7

The way forward: Targets and timelines for regulatory action .......................................................... 10

Conclusion ........................................................................................................................................... 14

References .......................................................................................................................................... 15

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Artemisinin-based monotherapy and risk for drug resistance

of Plasmodium falciparum

In 2012, there were an estimated 207 million cases2 of malaria around the world, causing an esti-mated 627 000 deaths,3 mainly among children under 5 years of age in Africa. Most malaria deaths occur as a result of infection with the P. falciparum parasite (2). WHO recommends five artemisinin-based combination therapy products as the mainstay of treatment for uncomplicated P. falciparum malaria: artemether/lumefantrine, artesunate/amodiaquine, artesunate/mefloquine, artesunate/ sulfadoxine-pyrimethamine and dihydroartemisinin/ piperaquine (1). In these products, the fast-acting artemisinin derivative is combined with a second, longer-acting antimalarial partner medicine to kill the parasite by two different modes of action, thus delaying the development of resistance. Preventing the development and spread of artemisinin resistance is crucially important, as no alterna-tive antimalarial medicines offering equivalent levels of efficacy and safety are expected to become available in the short-term (3).

Oral artemisinin-based monotherapy. Artemisinin and its derivatives are highly effective. They rapid-ly eliminate asexual parasite stages and early sexual forms of falciparum malaria, producing a rapid clinical and parasitological response (4). When used as monotherapy, i.e. against WHO recommenda-tion without a partner medicine, artemisinin derivatives would have to be taken for seven days in order to achieve a high cure rate; a 3-day treatment results in an unacceptably high (48–54%) recrudescence rate (5). The full 7-day treatment is, however, found to be impracticable by most patients, who tend to discontinue treatment early, resulting in recrudescence and resistance.

There are two main product presentations available on the markets which promote the spread of artemisinin resistance: (i) medicinal products with variable duration of treatment, ranging between three and seven days with an artemisinin-based monotherapy only; and (ii) ACTs whose two partner medicines are co-blistered and present as individual tablets rather than being co-formulated (i.e. fixed-dose combinations). Patients tend to take only a 3-day treatment with the artemisinin component of co-blistered ACT products and to discard the partner medicine (often amodiaquine, mefloquine or sulfadoxine-pyrimethamine) because of the poor tolerability of these latter medicines. When used inappropriately, both product presentations lead to low-dose monotherapy with an artemisinin derivative, exposing the parasite to sub-therapeutic blood levels. This promotes the spread of parasite resistance by eliminating the most sensitive parasite strains and leaving the more resistant ones to multiply unrestrained. The same mechanism applies to sub-standard products that do not meet quality requirements, as they often contain low or sub-therapeutic levels of the active pharmaceutical ingredient (API), due to either a low content, inadequate dissolution or poor stability (leading to degradation of the API).

Emergence and selection of drug-resistant parasites. The emergence of resistance to antimalarial medicines is initiated by rare spontaneous mutations that give survival advantages to the parasite when exposed to a specific antimalarial compound. When exposed to the medicine in question (“drug pressure”), the mutant parasite strains that have a survival advantage are selected in favour of sensi-tive strains. Mutations can originate in populations of parasites from the same geographical area or in parasites from different areas. Migrating populations contribute to the development and spread of resistance by introducing parasites with resistance mutations from other geographical areas, leading to a new pool of mutated and recombined parasites in a certain geographical area. Antimalarial immunity in patients, which increases in proportion to the intensity of malaria transmission, might conceal the effects of drug resistance and delay the detection of drug-resistant infections (6).

2. Source: World Malaria Report 2013; uncertainty range: 135–287 million 3. Source: World Malaria Report 2013; uncertainty range: 473 000–789 000

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Latest evidence on artemisinin resistance

P. falciparum has thus far developed resistance to all classes of medicines used in its treatment (6). While quinine remained effective for decades after its wide-scale introduction in the early twentieth century, resistance to the other antimalarial compounds emerged faster, varying from 12 years for chloroquine (1945–1957), to 5 years for mefloquine (1977–1982) and to approximately 1 year for proguanil (1948–1949), sulfadoxine-pyrimethamine (1967) and atovaquone (1996). In the 1950s and 1960s, resistance to chloroquine and sulfadoxine–pyrimethamine was first detected in P. falciparum in Pailin province, western Cambodia (4), from where it subsequently spread to the Indian subcon-tinent in the 1970s and then to East Africa in the 1980s.

In 2008, scientists confirmed the first cases of falciparum resistance to artemisinin derivatives, also in the province of Pailin (7). In this area, artemisinins were extensively used as monotherapy during the past decade, which may have contributed to the development of resistance, with other, unidentified factors (4, 8). Today, there is great concern that artemisinin resistance may spread beyond the Greater Mekong sub-region or emerge independently on other continents.

The WHO Global Malaria Programme published the latest status report on artemisinin resistance in January 2014 (9). Foci of artemisinin resistance have meanwhile been identified in five countries in the Greater Mekong subregion, mainly along international borders: Cambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam. Additional foci of artemisinin resistance are suspected in Suriname, Guyana and French Guiana (France); the initial findings are pending confirma-tion by in-depth studies in the three areas.

Global surveillance of artemisinin resistance is expected to be facilitated by a recently identified molecular marker: mutations in the Kelch 13 (K13) propeller domain have been shown to be associ-ated with delayed parasite clearance both in vitro and in vivo. More information on artemisinin resistance is available on the Global Malaria Programme web page at www.who.int/malaria/publications/atoz/status_rep_artemisinin_resistance_jan2014.pdf.

Drug pressure and its impact on resistance to antimalarial medicines

Experience shows that, once resistance has developed, removal of drug pressure can prolong the life span of the corresponding medicine, i.e. the time the medicine is still effective against the disease (10). Mutations for drug resistance in P. falciparum generally affect the parasite’s fitness. Studies with chloroquine and mefloquine showed that parasites’ susceptibility to the corresponding API was re-stored after use of the medicines was discontinued, as the resistant mutations also affected the fitness and survival of the malaria parasites. In China, in vivo resistance to chloroquine decreased over 5–8 years from more than 84% to 40%. In certain regions of Malawi, the first African country to discontinue use of chloroquine in 1993 in favour of sulfadoxine–pyrimethamine, the molecular mark-ers of chloroquine-resistant parasites decreased in prevalence over time (10). Mutations conferring resistance to other antimalarial medicines, such as sulfadoxine–pyrimethamine, may, however, persist after drug pressure is removed, as these mutations apparently do not affect the parasite’s fitness. Secondary mutations may occur, providing a compensatory mechanism to improve the para-site’s fitness in the presence of resistant mutations. Preliminary evidence indicates that the genetic mutations associated with delayed response to artemisinin and its derivatives have negative effects on the fitness and survival of P. falciparum.

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WHO recommendations on phasing out oral artemisinin-based

monotherapy

On the basis of the biological mechanisms of resistance observed with the other antimalarial com-pounds, it is expected that the removal of oAMT products will help slow down the spread of P. falciparum resistance to artemisinins and that the prevalence of newly emerged resistant strains might decline over time. Both mechanisms will extend the useful therapeutic life of artemisinin derivatives.

WHO therefore urges Member States to cease the marketing and use of oAMT products (see defini-tion in the box below) in the public and private sectors and to promote the rational use of ACT. This recommendation was endorsed by all WHO Member States at the Sixtieth World Health Assembly in May 2007, in resolution WHA60.18 (11), and it was reaffirmed in 2011 in resolution WHA64.17 (12). Since 2006, the Global Malaria Programme has contacted all major procurement and funding agencies in relation to these recommendations; as a result, all major agencies have discontinued funding for and procurement of these medicines. Table 1 lists the main initiatives undertaken by WHO over the past few years to phase out oAMT as part of global strategies to contain the development and spread of artemisinin resistance.

Oral artemisinin-based monotherapy

The recommendation to phase out artemisinin-based monotherapy refers only to oral formulations. Rectal and injectable formulations (e.g. artesunate suppositories and artesunate injectables) are still required for pre-referral treatment and for the treat-ment of severe malaria, respectively (1). In exceptional cases, the manufacture and export of oAMT might still be necessary for co-packaging with a partner medicine in ACT products that are not yet available as fixed-dose combinations.

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Table 1. Main initiatives by WHO to phase out oral artemisinin-based monotherapy (oAMT) as part of global strategies to contain the development and spread of artemisinin resistance

Year Initiative Content or activities

2006 WHO requests cooperation of major funding and procure-ment agencies

Since 2006, the Global Malaria Programme has contacted the major procurement and funding agencies in relation to recommendations on oAMT, and all the agen-cies have progressively discontinued funding for and procurement of these medicines.

2007 World Health Assembly resolution WHA60.18, Geneva, May 2007

WHO urges Member States to cease the marketing and use of oAMT in both the public and private sectors and to promote the use of artemisinin-based combina-tion therapy (full text of the resolution available at http://www.who.int/malaria/publications/WHA-malaria-resolution-2007.pdf).

2007 WHO informal consultation with manufacturers of artemisinin-based pharmaceu-tical products used for treat-ment of malaria, Geneva, August 2007

Second WHO informal consultation to present to manufacturers current evidence on the development of resistance to artemisinin and its derivatives and to review with manufacturers progress made and challenges in reducing the availability of oAMT on the market (full meeting report available at http://www.who.int/malaria/publications/atoz/manufacturers_artemisinin_products/en/).

2010 Publication of article “Regula-tory action needed to stop the sale of oral artemisinin-based monotherapy” in WHO Drug Information

Article providing the latest evidence on artemisinin resistance and a generic guide for regulatory authorities to undertake action to withdraw oAMT from the market (full article available at http://www.who.int/malaria/generic_guide_regulatory_action.pdf).

2010 International Conference of Drug Regulatory Authorities, Singapore, December 2010

A forum for regulatory authorities of WHO Member States to discuss ways to strengthen collaboration, to exchange information and to formulate collaborative approaches to issues of common concern. The 2010 conference, with approxi-mately 400 participants from approximately 90 countries, concluded with a recommendation on “regulatory actions to contain artemisinin resistance. National regulatory authorities should take appropriate action to enforce the implementa-tion of resolution WHA 60.18 concerning the suspension of marketing and use of oAMT.”

2011 World Health Assembly resolution WHA64.17, Geneva, May 2011

In order to sustain the advances in malaria control, WHO urges Member States to take immediate action to contain resistance to artemisinin-based medicines, by strengthening regulatory services in the public and private sectors, working to halt the use of oAMT and substandard medicines that do not meet WHO prequalifi-cation standards or strict national regulatory authority standards, introducing quality-assurance mechanisms and improving supply-chain management for all malaria commodities and services (full text of the resolution available at http://www.who.int/malaria/publications/WHA-malaria-resolution-2011.pdf).

2011 Global plan for artemisinin resistance containment

The Global Plan was developed in response to the identification of artemisinin resistance in the border region between Cambodia and Thailand and to concern that it could spread or emerge spontaneously elsewhere. The main objective is to protect ACT as an effective treatment for P. falciparum malaria. It identifies three tiers of containment activities and recommends phasing out oAMT (full document available at http://www.who.int/malaria/publications/atoz/9789241500838/en/).

2013 Emergency response to artemisinin resistance in the Greater Mekong sub-region, regional framework for action 2013–2015

The framework urges partners to coordinate malaria interventions for all at-risk groups, to achieve tighter coordination and management of field operations, to obtain better information for containing artemisinin resistance and to strengthen regional oversight and support. It also recommends phasing out oAMT (full document available at http://www.who.int/malaria/publications/atoz/9789241505321/en/).

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Monitoring enforcement of regulatory action on artemisinin-based

monotherapy

Web-based WHO monitoring system. In order to track compliance with resolution WHA60.18, the WHO Global Malaria Programme has established a web-based monitoring system that contains regularly updated information on:

pharmaceutical companies that market oAMT (http://www.who.int/malaria/monotherapy_manufacturers.pdf) and

regulatory actions undertaken by national medicines regulatory authorities (http://www.who.int/malaria/monotherapy_NDRAs.pdf).

Pharmaceutical companies. Since 2005, WHO has identified about 100 pharmaceutical companies involved in the production and marketing of oAMT (the figure is probably far higher). The information provided on the web page is derived from product catalogues published on the web, from printed advertisements in English and French, and from samples of finished pharmaceutical products available to WHO. The list is not complete, as many companies do not post their products on the web-site or do not make the information available in English or French. Moreover, this information changes over time and is no longer available on the websites of a number of companies identified by WHO between 2005 and 2010. The names of these companies have been removed from the WHO website, although it is not clear whether they were still involved in the production and marketing these products. At present, the positions of 86 companies are reflected in the tracking tool: 56 companies have since withdrawn oAMT from the market, while the remaining 30 manufacturers have not yet disclosed their intention to do so to WHO. WHO contacts companies regularly on the basis of the information collected to clarify their positions with regard to WHO recommendations.

Nearly all companies that have a consistent market share in public sector procurement funded by international agencies have de-listed oAMT from their product catalogues; however, smaller compa-nies, which mainly target private sector markets, generally ignore WHO appeals. When responsible companies comply with WHO recommendations and withdraw their monotherapy products, they leave “niche markets”, which are rapidly exploited by opportunistic companies that manufacture monotherapy and substandard products. Figure 1 shows that most of the 30 companies known by WHO to be still involved in marketing oAMT are located in India, followed by Nigeria, China and Pakistan.

Figure 1. Manufacturing sites or places of registration of companies involved in marketing oAMT

(last updated 30 January 2014)

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Regulatory authorities. One of the main determinants of successful phase-out of oAMT is the setting of regulations by national medicine regulatory authorities in malaria-endemic countries. As of February 2014, of the 78 national medicines regulatory authorities of falciparum-endemic countries, 69 have either never registered or have taken regulatory measures to withdraw marketing authorization for oAMT, whereas nine still do not yet comply with WHO recommendations. Figure 2 shows the progress in withdrawing marketing authorization for oral artemisinin-based antimalarial medicines by national medicine regulatory authorities since 2006. As illustrated in Figure 3, most of the countries that have not yet taken regulatory steps to withdraw oAMT from their markets are located in the WHO African Region (Angola, Cape Verde, Equatorial Guinea, Gambia, Sao Tome and Principe and Swaziland), followed, with one country each, by the Eastern Mediterranean Region (Somalia), the South-East Asian Region (Timor-Leste) and the Region of the Americas (Colombia).

Figure 2. Progress in regulatory action to withdraw oAMT from the market (January 2006– January 2014)

Figure 3. Countries that still allow marketing of oAMT, by WHO region (last updated 12 February 2014)

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Regulation of pharmaceutical markets in malaria-endemic countries is complex. A number of coun-tries have succeed in phasing out oAMT, showing successful leadership of the national regulatory authorities by adopting WHO recommendations and adapting them to the national context:

Cameroon and Côte d’Ivoire, with their new regulations, aim to align the availability of products for sale in the private sector with those listed in the national treatment guidelines and available in the public sector.

Benin used the opportunity to remove not only oAMT but also all formulations of chloroquine, which were no longer effective because of high levels of P. falciparum resistance. Enforcement of the new regulations in Benin was timed with plans for large-scale deployment of ACTs.

In China and Viet Nam, the main aim of decisions by the national health authorities has been to remove oAMT from the public sector, following changes in national treatment guidelines.

Activities in India and Pakistan show the importance of coordinating the initiative by the national regulatory authorities and of support by the national malaria control programme and WHO. India also provides a clear example of the effectiveness of close coordination between federal and state medicine regulatory authorities. Although the Drug Controller General India announced regulatory steps to phase out oAMT with effect from July 2009 at Federal level, WHO identified 23 pharmaceutical manufacturers in India still involved in the production and marketing of these products at the beginning of 2011. More than 50% of the identified companies were located in one state, Maharashtra. Following communication between WHO and the Commissioner of the Food and Drug Administration Maharashtra, the order by the Drug Controller General India was adopted at State level in May 2011, leading to the withdrawal of oAMT produced in Maharashtra State.

Burundi actively recalled existing stocks of chloroquine and sulfadoxine–pyrimethamine once artesunate/amodiaquine was introduced and deployed as the new first-line treatment for uncomplicated falciparum malaria.

Cambodia and Malawi used a more comprehensive approach: both countries withdrew and sus-pended the marketing and manufacture of and the issuance of import licenses for oAMT. In addi-tion, Cambodia used active search and confiscation of all oAMT from the market, using enforce-ment laws. Malawi disposed of all oAMT on the market and followed this up with quarterly inspections of all medicine outlets in the private sector.

Availability of oAMT. Despite substantial progress on the regulatory side and good cooperation of a number of pharmaceutical manufacturers, continuous monitoring is required to ensure that oAMT are no longer available on the market. A few years ago, ACTwatch4 conducted surveys in 10 malaria-endemic countries: Benin, Cambodia, the Democratic Republic of the Congo, Kenya, Madagascar, Myanmar, Nigeria, Uganda, the United Republic of Tanzania and Zambia. Figure 4 shows the avail-ability of oAMT in the private sector market of the Democratic Republic of the Congo (40.5% in 2009) and Nigeria (35% in 2011). The regulatory decision taken by the National Agency for Food and Drug Administration and Control in Nigeria was limited to refusing new registrations of oAMT products, without suspending existing marketing authorizations.

4. A research project of Populations Services International in partnership with the London School of Hygiene and Tropical Medicine.

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Figure 4. Private sector availability of oAMT in the Democratic Republic of the Congo (DRC; 2009) and Nigeria (2011)

Source: Reproduced from ACTwatch 2011 outlet survey results for Benin, Madagascar, Nigeria Uganda and Zambia and 2009 outlet survey data for the Democratic Republic of the Congo.

The way forward: Targets and timelines for regulatory action

Active withdrawal of a medicine from the market in the interests of public health—in this case to limit the risk for development of resistance—through a regulatory approach is unprecedented. The produc-tion of artemisinin-based medicines is complex and comprises a number of steps, from planting seeds to extraction of the APIs from the plants’ leaves, derivatization and subsequent manufacture of the finished pharmaceutical products (FPPs). Consequently, the marketing and sale of oAMT involves complex domestic and international market dynamics and regulatory frameworks, including agricul-tural production, extraction of raw materials, derivatization, manufacture of APIs and FPPs. As seen in several countries, a variety of interventions can be used successfully to interrupt the manufacture, export, import, sale and use of oAMT. Figure 5 provides an overview of measures that can be adapted to phasing out both APIs and FPPs of oAMT from both export and domestic markets.

Figure 5. Regulatory targets for phasing out oAMT

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Domestic markets. To protect domestic markets, the most effective strategy is to stop import licenses and to refuse marketing authorization for such products. Domestic manufacturers should be regu-lated more stringently with regard to import licenses for APIs, for instance refusing API import licenses to companies that manufacture only oAMT. In addition, FPP import licenses should be sus-pended for companies that market only oAMT in order to prevent the re-packaging or re-branding of artemisinin-based FPPs produced in other countries.

It is crucial to ensure the wide-scale availability of ACTs in both the public and the private sector before oAMT can effectively be removed from the market.

Export markets. Many countries have protected their domestic markets as described above; however, the manufacture and export of oAMT have not been regulated with the same stringency. Conse-quently, oAMT products continue to be manufactured for export only and can easily enter malaria-endemic countries that have weak regulatory environments. It is crucial, therefore, that countries protect not only their domestic markets but also their export markets by withdrawing manufacture and export licenses.

Table 2 lists generic targets and suggested timelines, derived from successful experiences, for pro-gressive removal of oAMT from the market, which countries can adapt to their situations. Table 2. Generic guide with suggested timelines for phasing out oAMT medicines from the market

Action Task Suggested approximate timeline

Step 1 Agreement on time frame for phasing out oAMT in synchrony with wide-scale deployment of ACTs

Immediate

Step 2 Suspension of new approvals of marketing authorizations for oAMT

Immediate

Step 3 Suspension of import licences for artemisinin or its derivatives (as API or FPP) to domestic companies that

exclusively market oAMT

3–4 months

Step 4 Wide-scale deployment of ACTs in the public sector and communication to prescribers and consumers

to move away from monotherapy

Time X

Step 5 Widespread availability and affordability of ACTs in the private sector

Time Z

Step 6 Withdrawal of marketing authorization and of manufacturing licences for oAMT as FPPs to protect domestic markets

6 months after time X

Step 7 Suspension of export license for oAMT as FPPs to protect export markets

6 months after time X

Step 8 Active recall of oAMT from the market 3 months after time Z

Step 9 Enforcement activities (e.g. regular outlet inspections, confiscation and destruction of products, suspension

of selling licenses, fines, prosecution)

Regular intervals after step 8

Step 10 Monitoring to ensure complete elimination of oAMT as FPPs from the market

10–12 months after time X

oAMT, oral artemisinin-based monotherapy; ACT, artemisinin-based combination therapy; API, active pharmaceutical ingredient; FPP, finished pharmaceutical product; time X, time at which a country will deploy ACT in the public sector on a wide scale (All subsequent timelines are conditional on this.); time Z, requires distribution of high-quality ACT at subsidized prices in the private sector.

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A number of challenges have been encountered in the implementation of regulatory actions at coun-try level, particularly in countries with a federal state structure: while appropriate regulatory decisions were endorsed at the federal level, an adequate enforcement mechanism was required at the state level to adopt and implement the same regulations. India, for example, took regulatory steps to with-draw oAMT from the market in 2008–2009; however, regulatory action followed in only a few states, and the largest number of oAMT manufacturers continue to be located in India (see Figure 1).

Table 3, based on the generic guide to phase out oAMT, summarizes the minimum requirements for tracking the progress of essential regulatory action by national authorities in the form of a checklist. Table 4 lists the main factors in the development and spread of artemisinin resistance that must be taken into consideration when phasing out oAMT from the market; it also offers a range of potential solutions. Table 3. Checklist for monitoring regulatory action taken by national authorities to phase out

oAMT from domestic and export markets

Regulatory action Protection of domestic market Protection of export market

Marketing authorization No more approvals of new marketing authorization for oAMT FPPs

Suspension of existing marketing authorizations for oAMT FPPs

Manufacturing licenses Suspension of manufacturing licenses for oAMT FPPs

Import licenses Suspension of API and oAMT FPP import licences for companies exclusively marketing oAMT or exclusively involved in re-packaging or re-branding

Export licenses Suspension of export licenses for APIs with clear documentation they are exclusively used for the manu-facture of oAMT

Suspension of export licenses for oAMT FPPs

Wide-scale availability of affordable, quality ACT products

Public sector

Private sector

(informal private sector)

Active recall and disposal of existing oAMT stocks from all outlets

Public sector

Private sector

(informal private sector)

Regular inspection of outlet systems

Public sector

Private sector

(informal private sector)

Regular inspection of manufacturing sites

Harmonization of regula-tions at state and federal levels (where applicable)

Public sector

Private sector

(informal private sector)

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Table 4. Main factors that contribute to the development and spread of artemisinin resistance and potential solutions

Factor Issue Potential solution

Patient compliance and adherence to treatment

Artemisinin-based monotherapy requires a full 7-day treatment course.

Patients often discontinue treatment too early because of rapid clearance of symptoms within 3 days by the artemisinin derivative.

Sub-therapeutic levels of API cannot fully clear parasitaemia.

• Use ACT medicines that require only a 3-day treatment regimen.

• Provide comprehensive information resulting in patient compli-ance to the full treatment course.

• Ensure widespread accessibility to affordable, quality, ideally fixed-dose ACTs.

• Eliminate oAMT from the market.

Co-formulated products

Co-blistered packs of artemisinin derivative and partner medicine.

Rapid clearance of symptoms without complete parasite clearance by the artemisinin derivative and poor tolerability of the partner medicine result in patients often taking only the artemisinin compo-nent of the co-blister.

Sub-therapeutic levels of API cannot fully clear parasitaemia.

• Use fixed-dose ACT (co-formulated products containing e.g. both partner medicines in one tablet).

• Widespread availability of and accessibility to affordable, quality, fixed-dose ACT.

Quality of medicines Products containing inadequate amounts of the API due to e.g. poor stability or degradation.

Sub-therapeutic levels of API cannot fully clear parasitaemia.

• Select pre-qualified antimalarial medicines for procurement.

• Ensure functioning quality assurance and quality control measures at country level.

Migrating populations Mutated parasites from other geographical areas are imported, which then recombine with local parasites to give rise to a pool of mutated and recombined parasites.

Contribution to development and spread of resistance.

• Increase monitoring and surveillance, with specific attention to mass population movements from areas with high levels of resistance.

• Improve access to rational treatment with ACT.

Weak regulatory systems

Lack of adequate mechanisms at country level to ensure that only high-quality medicines enter the market.

• Strengthen national medicine regulatory systems.

• Build capacity and introduce structural reforms.

Information Insufficient knowledge of both prescriber and patient. • Adequate training and communication to change prescribing habits.

• Information campaigns for patients.

Availability of ACTs Insufficient amounts of quality ACT at affordable prices. • Ensure wide-scale availability of affordable, quality ACT and rapid diagnostic tests in both public and private sectors to crowd out oAMT and promote rationale use of ACT.

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Conclusion

The loss of artemisinin derivatives will have devastating consequences on people’s health in malaria-endemic countries and also threaten recent progress in malaria control achieved in many countries. In view of the latest evidence on artemisinin resistance and in the absence of safe, effec-tive alternative medicines for the treatment of P. falciparum malaria, urgent action is required to protect this important class of life-saving medicines. Prevention of the development and spread of artemisinin resistance is crucially important, and oAMT must be withdrawn entirely from the market.

A range of interventions by regulatory authorities at country level show that phasing out oAMT medicines from malaria-endemic countries is possible. It is essential to ensure the widescale availa-bility of affordable, quality ACT in both the public and the private sector and at the same time to apply enforcement mechanisms to stop the introduction of new oAMT products onto the market and to recall existing oAMT stocks in countries. Success in phasing out oAMT from the market depends ultimately on effective regulation of medicines at country level, to protect both the domestic and the export market, targeting manufacture, import and export licensing of these prod-ucts. A flourishing informal private sector, which in many malaria-endemic countries still continues to provide oral monotherapy to clients, must be counteracted by improving access to quality medi-cines at affordable prices through a functional supply management system.

Experience shows that a number of critical steps should be taken in phasing out oAMT from the market. It is essential to synchronize these steps with widescale deployment of quality ACT in the public sector and to set reasonable timelines that allow progressive adaptation and response of the private sector to the new health directives. Government commitment and strong stewardship by national regulatory authorities are crucial to achieving this.

Artemisinin resistance, which is being fuelled by the use of oral monotherapy products, is too seri-ous a public health risk to allow their continued use.

For more information please contact: Silvia Schwarte Global Malaria Programme World Health Organization Tel: +41 (0) 22 791 5042 Email: schwartes@who.int

Please also visit the following WHO website for additional information and data: www.who.int/malaria/areas/treatment/withdrawal_of_oral_artemisinin_based_monotherapies/en/

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