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 oAMT
1
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 peoples
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.

Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 2
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



Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 3
Artemisinin-based monotherapy and risk for drug resistance
of Plasmodium falciparum
In 2012, there were an estimated 207 million cases
2
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 (4854%)
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: 135287 million
3. Source: World Malaria Report 2013; uncertainty range: 473 000789 000

Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 4
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 (19451957), to 5 years for mefloquine (19771982) and to approximately 1 year for
proguanil (19481949), sulfadoxine-pyrimethamine (1967) and atovaquone (1996). In the 1950s and
1960s, resistance to chloroquine and sulfadoxinepyrimethamine 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 Peoples
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 parasites 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
58 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 sulfadoxinepyrimethamine, the molecular mark-
ers of chloroquine-resistant parasites decreased in prevalence over time (10). Mutations conferring
resistance to other antimalarial medicines, such as sulfadoxinepyrimethamine, may, however,
persist after drug pressure is removed, as these mutations apparently do not affect the parasites
fitness. Secondary mutations may occur, providing a compensatory mechanism to improve the para-
sites 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.

Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 5
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.

Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 6
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_produ
cts/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
20132015
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/).

Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 7
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 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)











Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 8
Regulatory authorities. One of the main determinants of successful phase-out of oAMT is the setting
of regulations by national drug 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
drug 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)



Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 9
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 Cte dIvoire, 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 drug regulatory authorities. Although the Drug Controller General India announced regula-
tory 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 sulfadoxinepyrimethamine 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 drug 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, ACTwatch
4
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.

Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 10
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 healthin this case to limit
the risk for development of resistancethrough 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













Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 11
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
34 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
1012 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.

Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 12
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 20082009; 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 market-
ing 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 ex-
clusively involved in re-packaging
or re-branding

Export licenses Suspension of export licenses
for APIs with clear documenta-
tion they are exclusively used
for the manufacture 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)


Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 13
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 drug 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.

Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 14
Conclusion
The loss of artemisinin derivatives will have devastating consequences on peoples 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/





Withdrawal of oral artemisinin-based monotherapies 1 May 2014 | 15
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