Review
Poor-quality antimalarial drugs in southeast Asia and
Lancet Infect Dis 2012;
12: 488–96
This online publication
has been corrected.
The corrected version first
appeared at thelancet.com/
infection on May 22, 2012
Fogarty International Center
(G M L Nayyar BS, J G Breman MD,
J Herrington PhD), National
Institutes of Health,
Bethesda, MD, USA; Wellcome
Trust-Mahosot Hospital-Oxford
University Tropical Medicine
Research Collaboration,
Microbiology Laboratory,
Mahosot Hospital, Vientiane,
Laos (P N Newton MRCP); and
Centre for Clinical Vaccinology
and Tropical Medicine, Churchill
Hospital, Oxford University,
Oxford, UK (P N Newton)
Correspondence to:
Miss Gaurvika M L Nayyar,
Fogarty International Center,
National Institute of Allergy and
Infectious Diseases, National
Institutes of Health, Bethesda,
MD 20892, USA
gaurvika@gmail.com
488
sub-Saharan Africa
Gaurvika M L Nayyar, Joel G Breman, Paul N Newton, James Herrington
Poor-quality antimalarial drugs lead to drug resistance and inadequate treatment, which pose an urgent threat to
vulnerable populations and jeopardise progress and investments in combating malaria. Emergence of artemisinin
resistance or tolerance in Plasmodium falciparum on the Thailand–Cambodia border makes protection of the
effectiveness of the drug supply imperative. We reviewed published and unpublished studies reporting chemical
analyses and assessments of packaging of antimalarial drugs. Of 1437 samples of drugs in five classes from seven
countries in southeast Asia, 497 (35%) failed chemical analysis, 423 (46%) of 919 failed packaging analysis, and
450 (36%) of 1260 were classified as falsified. In 21 surveys of drugs from six classes from 21 countries in sub-Saharan
Africa, 796 (35%) of 2297 failed chemical analysis, 28 (36%) of 77 failed packaging analysis, and 79 (20%) of 389 were
classified as falsified. Data were insufficient to identify the frequency of substandard (products resulting from poor
manufacturing) antimalarial drugs, and packaging analysis data were scarce. Concurrent interventions and a
multifaceted approach are needed to define and eliminate criminal production, distribution, and poor manufacturing
of antimalarial drugs. Empowering of national medicine regulatory authorities to protect the global drug supply is
more important than ever.
Introduction characterised by slow rates of parasite clearance after
3·3 billion people are at risk of malaria, which is endemic treatment.14 Although a causal relation between poor-
in 106 countries. Between 655 000 and 1·2 million people quality artemisinin derivatives and artemisinin resistance
die every year from Plasmodium falciparum infection.1,2 has not been confirmed, modelling analyses suggest that
Much of this morbidity and mortality could be avoided if underdosing of patients can play an important part in the
drugs available to patients were efficacious, high quality, spread of resistance.15
and used correctly. Children in sub-Saharan Africa and Poor-quality antimalarial drugs are very likely to
southeast Asia have the highest risk of contracting and jeopardise the unprecedented progress and investments
dying from malaria. The global burden of malaria has in control and elimination of malaria made in the past
reduced in the past decade,3 and endemic countries decade. In this Review we assess the issue of poor-quality
are reliant on the long-term availability of effective antimalarial drugs, particularly the artemisinins, empha-
antimalarial drugs to maintain this progress.4 sise the mechanisms that determine their existence and
In endemic regions, antimalarial drugs are widely effect in sub-Saharan Africa and southeast Asia, and
distributed and self-prescribed (incorrectly and correctly) describe potential interventions to combat this problem.
for the many febrile episodes attributed to malaria.
Insufficient facilities to check the quality of antimalarial Definitions of drug quality
drugs, poor consumer and health-worker knowledge We obtained data for samples in two categories: drugs
about these drugs, their cost, and the paucity of failing chemical assay analysis and drugs failing package
appropriate regulatory and punitive action makes these testing; these categories were not mutually exclusive. No
drugs attractive targets for counterfeiters.5,6 Reports of universally accepted definitions exist for the different
poor-quality antimalarial drugs have increased in the types of poor-quality drugs and national terminologies
past decade, partly because of growing awareness and are diverse. Some nations, and some of those involved in
concern;6–8 however, the issue may be much greater than intellectual property law, are concerned that the word
it seems because most cases are probably unreported, counterfeit could wrongly lead to the classification of
reported to the wrong agencies, or kept confidential by some legitimate generic drugs as such, thus creating
pharmaceutical companies.6,9–10 Of the many public much debate about terminology.16 WHO’s executive
health consequences of poor-quality antimalarial drugs, board documents use the undefined and unwieldy term
drug resistance is a particular concern. Low concen- spurious/falsely-labelled/falsified/counterfeit medical
trations of active pharmaceutical ingredient in poor- products.17 As a simplified and neutral term, we use
quality antimalarial drugs can result in subtherapeutic falsified as a synonym for counterfeit, devoid of
concentrations of drug in vivo, which contributes to considerations of intellectual property. We classify poor-
the selection of resistant parasites.11,12 Artemisinin quality drugs into three main types: falsified (fraudulently
derivatives are the most effective drugs against malaria, manufactured with fake packaging and usually no or
and artemisinin-based combination treatments are the a wrong active pharmaceutical ingredient); substandard
recommended first-line treatments for P falciparum (products resulting from poor manufacturing with
malaria.12,13 Resistance or tolerance to artemisinin deriva- no intent to deceive, usually with inadequate or too
tives has been described in western Cambodia, and is much active pharmaceutical ingredient); and degraded
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 Review

(good-quality drugs that are degraded by poor storage
after leaving the factory).6,18,19 These definitions are based
on those used by WHO.18,20
Although packaging analysis is needed to determine
that a drug is falsified, obtaining a genuine package
sample with which to compare others is difficult.18
Therefore, when packaging analysis is not possible, we
assume that a drug containing no active pharmaceutical
ingredient, or an unstated drug or substance, is falsified.
Manufacturing failures that result in production and
release of legitimate drugs with no or wrong active
pharmaceutical ingredients have occurred21 but seem rare.
Both packaging and chemical analyses are needed to
classify drugs as substandard: such drugs are legitimate
and pass package inspection but fail chemical analysis
by pharmacopeia standards. We labelled drugs that
failed packaging authenticity analysis and those
containing none of the stated active pharmaceutical
ingredient, or an unstated drug or substance, as falsified.
Drugs that have been stored in poor conditions can
degrade faster than do those stored adequately, and
might have reduced active pharmaceutical ingredients
and increased toxicity.22,23 These drugs are difficult to
identify because very few chemical data are available that
allow poor-quality production to be distinguished from
chemical degradation after production.24 Definitive
research about degraded or expired antimalarial drugs is
scarce, and we do not include these drugs in our analysis.
Southeast Asia
From 1999 to 2010, seven multicountry surveys with
data from seven countries in southeast Asia included
chemical assays or packaging analysis for 1437 samples of
seven antimalarial drugs, including artemether, artesunate,
chloroquine, mefloquine, quinine, sulfadoxine–pyri-
methamine, and tetracycline. 1173 samples (82%) were
obtained with convenience sampling with no random-
isation of outlet selection. All studies used some form of
chemical analysis with one or more of the following
techniques: high-performance liquid chromatography,
thin-layer chromatography, liquid chromatography–mass
spectrometry, X-ray diffraction, disintegration analysis,
dissolution, colorimetric testing, and Raman spectroscopy
(table). 497 (35%) of 1437 samples failed chemical assay
analysis, 423 (46%) of 919 samples failed packaging
analysis, and 450 (36%) of 1260 samples were falsified
(table). Six of seven surveys had brief comments about
analysis of active pharmaceutical ingredient. Of the

Location Date of Drug tested Method of testing Obtained from Sampling Total Samples that failed Falsified*
sample technique samples testing
collection tested
Chemical Packaging
assay tests
analysis
Southeast Asia
Newton et al Cambodia, Laos, 1999– Artesunate HPLC, colorimetric Private pharmacies Convenience 104 39/104 31/84 39/104
(2001)9 Myanmar (Burma), 2000 testing (fast red dye), and outlets (38%)† (38%) (38%)
Thailand, Vietnam packaging analysis
Newton et al Cambodia, Laos, 1999– Artesunate HPLC, colorimetric Private pharmacies Convenience 391 196/391 195/391 195/391
(2008)25 Myanmar, Thailand- 2005 testing (fast red dye), and outlets and (50%) (50%) (50%)
Myanmar border, packaging analysis randomly‡
Vietnam
Dondorp et al Cambodia, Laos, 2002–03 Artesunate, artemether, HPLC, colorimetric Public and private Convenience 303 103/303 99/303 99/303
(2004)26 Myanmar, Thailand, dihydroartemisinin, testing (fast red dye), pharmacies and (34%); (33%) (33%)
Vietnam mefloquine packaging analysis outlets and 99/103
facilities (96)†
Lon et al Cambodia 2003 Artesunate, quinine, HPLC, thin-layer Public and private Convenience 451 122/451 72/111 88/111
(2006)27 chloroquine, tetracycline, chromatography, pharmacies, and (27%); (65%) (79%)§
mefloquine packaging analysis, outlets and 30/122
disintegration analysis facilities (25%)†
Sengaloundeth Laos 2003 Artesunate HPLC, colorimetric Private pharmacies Stratified 30 27/30 26/30 27/30
et al (2009)28 testing (fast red dye), and outlets random (90%) (87%) (90%)
mass spectroscopy, sampling
pollen analysis, X-ray
diffraction, packaging
analysis
United States China 2004 Artesunate, quinine, HPLC, thin-layer NS Convenience 39 2/39 Not 2
Pharmacopeia chloroquine, sulfadoxine- chromatography, visual (5%)† tested (5%)
(2004)29 pyrimethamine, inspection, dissolution
mefloquine analysis
Bate et al India 2008–09 Chloroquine Thin-layer Private pharmacies Systematic 119 8/119 Not NA
(2009)30 chromatography, and outlets random (7%) tested
disintegration analysis sampling
(Continues on next page)

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 Review

Location Date of Drug tested Method of testing Obtained from Sampling Total Samples that failed Falsified*
sample technique samples testing
collection tested
Chemical Packaging
assay tests
analysis
(Continued from previous page)
Sub-Saharan Africa
Ogwal-Okeng Uganda 2001 Chloroquine tablets and HPLC Private and public Convenience 92 57/92 Not NA
JO et al (2003)31 injections outlets (62%) tested
Basco et al Cameroon 2001 Chloroquine, quinine, Colorimetric test, Private pharmacies Convenience 284 112/284 Not 49/284
(2004)10 sulfadoxine- thin-layer only sampling (39%) tested (18%)
pyrimethamine chromatography from various
vendors
Amin et al Kenya 2002 Sulfadoxine- HPLC, dissolution tests Public and private Convenience 116 47/116 Not NA
(2005)32 pyrimethamine, outlets (41%) tested
amodiaquine
Thoithi et al Kenya 2001–05 Artemether, Tests of uniformity of Public and private Convenience 41 11/41 Not NA
(2008)33 dihydroartemisinin, weight, content of active outlets (27%) tested
quinine, sulfadoxine- pharmaceutical
pyrimethamine, ingredient, dissolution
amodiaquine
Atemnkeng Kenya and 2004 Artemether, arteether, HPLC with European Randomly, from Convenience 24 9/24 Not NA
et al (2007)34 Democratic artesunate, pharmacopeia standards both public and sampling of (38%) tested
Republic of Congo dihydroartemisinin private pharmacies different
or outlets forms of drug
Tipke et al Burkina Faso 2006 Artesunate, artemether Packaging analysis, Private and public Convenience 77 32/77 28/77 29/77
(2008)35 lumefantrine, quinine, disintegration analysis, pharmacies or (42%); (38%) (38%)
chloroquine, sulfadoxine- colorimetric tests, thin- outlets 1/32
pyrimethamine, layer chromatography, (3%)†
amodiaquine ultraviolet-visible
spectroscopy
US Madagascar, 2008 Artermisinin-combination Compendial quality Private and public Convenience 197 64/197 Not NA
pharmacopeia Senegal, Uganda treatment, sulfadoxine- testing according to US pharmacies and (32%) tested
(2009)36 pyrimethamine pharmacopeia standards outlets
WHO (2011)37 Ghana, Kenya, 2008 Artermisinin-combination Compendial quality Public and private Convenience 267 72/267 Not NA
Nigeria, Tanzania, treatment, sulfadoxine- testing according to US outlets (27%) tested
Ethiopia, Cameroon pyrimethamine pharmacopeia standards
Kibwage Kenya Not Sulfadoxine- Dissolution analysis Public and private Convenience 33 23/33 Not NA
(2005)38 provided pyrimethamine outlets (69%) tested
Jande et al Tanzania Not Sulfadoxine- Dissolution analysis Public and private Convenience 9 5/9 Not NA
(2006)39 provided pyrimethamine outlets (55%) tested
Taylor et al Nigeria Not Quinine, choroquine, HPLC with British Private and public Random 284 119/284 Not NA
(2001)40 provided sulfadoxine- pharmacopeia, pharmacies and (42%) tested
pyrimethamine, proguanil dissolution analysis outlets
Smine et al Senegal Not Choroquine, sulfadoxine- US pharmacopeia Public and private Random 27 15/27 Not NA
(2002)41 provided pyrimethamine standards for active outlets (56%) tested
pharmaceutical
ingredient testing
Minzi et al Tanzania Not Sulfadoxine- HPLC, dissolution tests Public and private Convenience 33 10/33 Not NA
(2003)42 provided pyrimethamine, outlets (30%) tested
amodiaquine
Maponga et al Gabon, Ghana, Not Choroquine, sulfadoxine- HPLC, dissolution Private and public Convenience 278 5–100%¶ Not NA
(2003)43 Kenya, Mali, provided pyrimethamine analysis, drug-specific pharmacies and tested
Mozambique, assays outlets
Sudan, Zimbabwe
Gaudiano et al Congo, Burundi, Not Quinine, choroquine, HPLC with US Mainly small, Convenience 28 16/28 Not 1/28
(2007)44 Angola provided sulfadoxine- pharmacopeia standards, private pharmacies (57%); tested (4%)
pyrimethamine, uniformity of mass, and outlets 1/16
mefloquine disintegration analysis (6%)†
Aina et al Nigeria Not Choroquine tablets, British pharmacopeia Public outlet Convenience 32 19/32 Not NA
(2007)45 provided syrups, and injections dissolution tests, active (59%) tested
pharmaceutical
ingredient assay,
disintegration tests
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 Review

Location Date of Drug tested Method of testing Obtained from Sampling Total Samples that failed Falsified*
sample technique samples testing
collection tested
Chemical Packaging
assay tests
analysis
(Continued from previous page)
Kaur et al Tanzania Not Artemisinins, quinine, HPLC and dissolution Private and public Random 301 38/301 Not NA
(2008)46 provided antifolates, sulfadoxine- analysis with US pharmacies and (12%) tested
pyrimethamine, pharmacopeia standards outlets
amodiaquine
Bate et al Ghana, Kenya, Not Artesunate, artemether, Thin-layer Private pharmacies Convenience 210 73/210 Not NA
(2008)47 Nigeria, Rwanda, provided dihydroartermisinin, chromatography or and outlets (35%) tested
Tanzania, Uganda artemether-lumefantrine, dissolution analysis
sulfadoxine-
pyrimethamine,
mefloquine, amodiaquine
Ofori-Kwakye Ghana Not Artesunate Colorimetric tests, Public and private Convenience 17 14/17 Not NA
et al (2008)48 provided disintegration tests, EU outlets (82%) tested
pharmacopeia standards
Onwujekwe Nigeria Not Artesunate, HPLC and dissolution Private and public Stratified 225 60/225 Not NA
et al (2009)49 provided dihydroartemisinin, analysis with US pharmacies and random (27%) tested
chloroquine, quinine, pharmacopeia standards outlets sampling
sulfadoxine-
pyrimethamine
Newton et al Burkina Faso, Chad, 2002- Artesunate, HPLC, mass spectroscopy, Pharmaceutical Convenience 59 35/59 26/36 14/59
(2011)8 Cameroon, DR 2010 dihydroartemisinin, pollen analysis, X-ray companies, private (59%); (72%) (24%)
Congo, Ghana, dihydroartemisinin- diffraction, packaging and public 11/35
Kenya, Nigeria, piperaquine artemether- analysis pharmacies (31%)*¶
Rwanda, Senegal lumefantrine,
artemether-amodiaquine,
amodiaquine, halofantrine

Data are n/N (%), unless otherwise indicated. Samples failing chemical assay analysis might have failed packaging analysis. HPLC=High-perfomance liquid chromatography. NS=not specified. NA=not
applicable.*Falsified is used as a synonym for counterfeit. †Samples with no active pharmaceutical ingredient. ‡115 samples from Laos were randomly selected. §Only tetracycline, quinine, and artesunate were
tested. ¶Varies substantially by drug and country; not included in analysis.

Table: Reports of poor-quality antimalarial drugs by region in southeast Asia and sub-Saharan Africa, 1999–2011

497 samples that failed chemical assay analysis, 170 (34%)
had no active ingredient, 21 (4%) had low active ingredient,
and for 306 (52%), the content was unreported.
Few data were available with which to estimate the
frequency of substandard drugs. Five studies9,25–28
assessed both packaging and chemical analysis of
antimalarial samples; three found no substandard
artesunate.9,26,28 One sample of artesunate from Cambodia
had genuine packaging, but low active pharmaceutical
ingredient, which suggests that it was substandard or
degraded.25 894 (62%) of 1437 samples were artemisinins.
Five studies9,25–28 did both packaging and chemical
analysis of artemisinins: 383 (43%) of 894 samples failed
chemical assay analysis, 351 (42%) of 845 samples failed
packaging, and we classified 353 (42%) of 845 samples as
falsified. All samples that failed packaging also failed
chemical assay analysis. Reports were too incomplete to
establish results for other antimalarial drugs.
Sub-saharan Africa
21 surveys from 21 countries in sub-Saharan Africa
involved chemical assay or packaging analysis for
2634 antimalarial samples, including amodiaquine,
artemotil, artemether, artemesinin-combination treat-
ments, artesunate, chloroquine, mefloquine, quinine,
proguanil, and pyrimethamine (table8,10,31–49). 796 (35%) of
2297 samples failed chemical analysis with one or more
of the techniques described above for southeast Asia
(table). Nine (45%) of 20 studies provided brief data for
the active pharmaceutical ingredient content of
antimalarial drugs. Of the 796 failed samples, 121 (15%)
had low active pharmaceutical ingredient and 25 (3%)
had excessive active pharmaceutical ingredient; for
650 samples (82%), details of active pharmaceutical
ingredient content were not reported. In Burkina Faso—
the only country in which packaging analysis was done—
about 35% of samples failed (table). On the basis of three
studies,10,35,44 79 (20%) of 389 samples were falsified (table).
Data were inadequate to identify substandard drugs in
sub-Saharan Africa. Of the 2297 samples analysed,
482 (21%) were artemisinins, 136 (28%) of which failed
chemical analysis. Reports were inadequate to identify
drug-specific results for antimalarial drugs other than
artemisinins. Studies in both southeast Asia and sub-
Saharan Africa had a median lag time of 3 years (range
0–6) between drug sample collection and publication.

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 Review
Discussion
Poor-quality antimalarial drugs are an immediate and
urgent threat in health facilities, pharmacies, grocery
stores, and homes, and are exposing patients, health-care
workers, and governments to increases in morbidity,
mortality, economic losses, and drug resistance. Anti-
malarial drugs comprise 25% of the drugs consumed in
malarious countries, and when these drugs are of poor
quality, they afflict the most vulnerable populations.6
Issues of poor quality are not limited to antimalarial
drugs, and extend to other pharmaceutical drugs and
health products worldwide. Reports of poor-quality rapid
diagnostic tests for HIV and malaria underscore the
importance of good-quality control of medical products
beyond drugs alone.50–52
Findings from this Review suggest that up to 36% of
antimalarial drugs collected in southeast Asia were
falsified, whereas in sub-Saharan Africa, a third failed
chemical assay analysis. The data available for poor-
quality antimalarial drugs have important limitations,
including the paucity of data for packaging analysis, the
inadequacy of convenience sampling, and the absence of
data from some key malarious countries. Because of
these limitations, these data suggest that, over the past
decade, there have been severe problems with the supply
Panel 1: Factors contributing to the production and trade
of poor-quality antimalarial drugs
• Widespread self-prescription
• Testing for their quality is difficult
• Trade occurs in free-trade zones or free ports with
minimum regulation
• National and global drug legislation is poor or absent,
with lax implementation and quality control and few legal
penalties
• Scarcity of political will and cooperation from
stakeholders
• Proliferation of small pharmaceutical companies without
adequate quality assurance
• Expensive drugs with large profit margins
• Poor consumer and health-care worker knowledge about
product authenticity
• Stockouts, thefts, and the erratic supply of antimalarial
drugs
Panel 2: Effect of poor-quality antimalarial drugs
• Increased morbidity and mortality
• Financial consequences for patients and their families,
health-care systems, and the pharmaceutical companies
producing the genuine product
• Loss of confidence in pharmaceutical brand, drugs,
pharmacies, and health-care providers
• Drug resistance—eg, loss of valuable drugs, false alarm of
resistance, undermining of drug-resistance studies
492
of antimalarial drugs. Panel 1 shows factors encouraging
the proliferation of poor-quality antimalarial (especially
falsified) drugs. Consumption of falsified antimalarial
drugs is related to self-treatment through the unregulated
private sector, the cost and inaccessibility of good-quality
antimalarial drugs, the scarcity of drug regulation, and
the absence of punitive measures for counterfeiters. The
economic incentives for criminals of drug falsification
surpass the risks involved in their production and sale.
Free trade zones with lax regulation promote increased
access to drugs and could be pathways for informal
agreements, illegal trade, corruption, and covert
practices.20,53,54 Legal approaches to combat falsified drugs,
where they exist, are only applicable nationally, which
makes penalising of international trade in falsified drugs
even more challenging. No universal jurisdiction allows
prosecution of international traders in falsified drugs.
No reliable global estimates are available about the
frequency of poor-quality antimalarial drugs because of
no internationally accepted definitions of different types
of poor-quality drugs; no globally standardised or
statistically robust sampling schemes, testing protocols,
and requirements for drug content; a dearth of funds;
and no recognised international forum to provide
technical and scientific guidance and oversight.
Although WHO gathers and disseminates information
about poor drug quality, this effort is hampered because
few countries submit such reports. In WHO’s Western
Pacific region, an innovative internet-based rapid-alert
system allows medicine regulatory authorities and other
bodies to share reports of poor-quality drugs;55 an
expansion of this system to other regions could be
highly effective. The World Wide Antimalarial
Resistance Network is developing an online method to
summarise data for poor-quality drugs and to make
such information readily available, thus facilitating
international discussions between medicine regulatory
authorities and national malaria control programmes.56
Guidelines for doing and reporting surveys about drug
quality are available and should be used widely.57
A survey of 26 African medicine regulatory authorities
indicates a lack of sustainable funding, chronic shortage
of qualified staff, and few or no operational resources.58
Of the 47 malarious countries in Africa, only Kenya,
South Africa, and Tanzania have WHO prequalified
laboratories that are equipped to chemically analyse
antimalarial drugs.59 Most of the published chemical
analyses have been done in high-income countries,
which causes delays in analysis and discourages country
ownership of the issue; however, until the international
community helps build capacity in malarious countries,
this option is the only alternative.22 Scarce quantitative
evidence defining the scope of substandard and falsified
drugs is an under-recognised issue that needs to be
addressed by more comprehensive analysis to distinguish
these drugs. Testing for falsified drugs is challenging
because of the expense and training needed to do surveys
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with chemical and packaging analysis, scarcity of
available rapid, cheap, roadside testing systems, and the
risks of investigation of criminal networks. Packaging
analysis to identify falsified antimalarial drugs was done
in only two of the 21 surveys in sub-Saharan Africa. Use
of packaging and chemical analysis to distinguish
falsified and substandard drugs is important because
their origins and solutions differ substantially.
To accurately detect poor-quality drugs, standardised
methods with good quality control, supporting tech-
nology, and trained well-supervised personnel are
essential in malaria-endemic regions. Colorimetric tests,
the Global Pharma Health Fund-Minilab, portable,
hand-held, and battery powered photometers, port-
able mass-spectrometers,60 Raman spectroscopy, and
near-infrared spectroscopy61 could empower pharmacy
inspectors in malarious countries to screen the drug
supply. Although the strengths and weaknesses of these
tests are known in the laboratory setting, conclusive
comparative field assessments are lacking.62
Besides their direct negative effect on patients and
their families, poor-quality drugs harm health workers
and services, pharmaceutical companies, governments,
and economies by increasing medical care and expense
for patients, and by reducing credibility of the health-
care system (panel 2). The data available do not suggest
definitive sources, supply-chain entry points, or coun-
tries as leading producers or distributors of poor-quality
antimalarial drugs. Poor-quality drugs are widely avail-
able and can be bought at local shops or online. Because
mechanisms involved in the production and sale of
substandard, falsified, and degraded drugs are so varied,
so are the sources of these drugs. However, confiscation
of falsified drugs led by Interpol programmes, such as
Jupiter, Storm, Mamba, and Pangea, provide some
insight into the range of criminals involved in such
trade.63 Production and distribution of counterfeit
antimalarial drugs should be prosecuted as crimes
against humanity.
Few data are available for quality of antimalarial drugs
in India30,64 and China.25,29 What little evidence is available
suggests that criminals in these countries are involved
in the production and international trade of falsified
drugs.65 Importantly, manufacturers of genuine anti-
malarial drugs in India and China (70 companies
identified by WHO)66 have been vital in the production
and export of affordable artemisinin-based antimalarial
drugs to African and Asian countries. Chinese and
Indian governments have run innovative campaigns to
restrict development and distribution of falsified
medicines, but much more needs to be done.67–69
Drug resistance has stymied previous attempts to
eradicate malaria and now threatens progress in global
efforts to control and eliminate this disease.3,4,70 Poor-
quality artemisinin-based drugs with subtherapeutic
active pharmaceutical ingredient could contribute to
artemisinin-resistant falciparum malaria, as described
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Review
Panel 3: A multifaceted approach to address the production of poor-quality
antimalarial drugs
• The 130th session of WHO’s Executive Board meeting in January, 2012, adopted the
resolution of member states to implement an intergovernmental mechanism, which,
among other objectives, will establish collaboration around compromised medical
drugs from a “public health perspective, excluding trade, and intellectual property
considerations”.17 This plan needs to be urgently enacted, yielding a global consensus
for definitions of poor-quality drugs and interventions to ensure that patients have
access to good-quality medicines. One step could be a treaty to facilitate
improvements in drug quality through international collaboration, possibly within
WHO’s framework.77
• Medicine regulatory authorities are key for implementation of interventions that will
improve drug quality. Urgent support is needed for the 30% of authorities that have
either no drug regulation, or a capacity that barely functions.78 Although global
economic problems make financial support difficult, the international community
should be encouraged to support expansion of technical and human capacity of
non-functional authorities. This issue is of increasing importance as manufacturing
and marketing of essential drugs and biologicals move to the developing world.
• Improved, internationally standardised research methods are needed for detecting
poor-quality drugs. Estimation of the frequency and extent of falsified, substandard,
or degraded antimalarial drugs needs samples to be obtained in a statistically valid
manner, and to be formally preserved. Standardised approaches to packaging of
investigations and chemical testing is hugely important.22 Routine, representative
national surveys of the supply chain and public markets will provide better national
estimates of poor-quality drugs and allow for assessment of interventions over time
and according to region. The delay between obtaining of samples, analysis, and
subsequent sharing of results with appropriate authorities needs to be minimised,
thus allowing timely action against criminals and poor manufacturers. Research
groups should be encouraged to submit results of surveys to the appropriate medicine
regulatory authorities and national malaria control programmes immediately after
testing and before publication.18
• Medicine inspectors need accurate, simple, and inexpensive rapid field-testing
methods to empower their inspections and facilitate surveys.22 Which of the many
rapid testing methods is most accurate and useful for different environments is
unclear.
• Educational and information exchange programmes via national media, health
systems, legislative and other networks is crucial to improvement in the knowledge of
patients, their families, and health-care workers.
• Ensuring of increased access to free or inexpensive quality-assured artemisinin-
combination treatments in both public and private sectors is likely to reduce the
financial incentives for criminal producers and encourage better manufacturing
standards. Whether programmes, such as Affordable Medicines Facility for Malaria,
improve the quality of antimalarial drugs that patients are given will be an important
consideration.
• Scarcity of leadership and coordination has been a major issue. Poor-quality drugs,
especially antimalarial drugs, must receive more recognition in multinational settings
because they are a real, immediate, and continuing threat to health and wellbeing.
The Millennium Development Goals have served as the leading forum to define
priorities for health globally.79 However, the Goals refer only to availability of HIV
drugs; they should address the issue of poor-quality drugs. Support for medicine
regulatory authorities needs strengthened leadership through WHO and the
International Conference of Drug Regulatory Authorities.80 An international
coordinating body is needed to facilitate data sharing, data mining, networking,
mutual capacity building, and analysis of the effect of drug regulation policies on
public health.
493
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Search strategy and selection criteria
We reviewed published literature and unpublished data from
1999 to Feb 20, 2012, for the chemical analysis and
packaging of antimalarial drugs in southeast Asia and
sub-Saharan Africa. We searched PubMed, WHO documents,
US Pharmacopeia databases, anticounterfeiting networks,
and unpublished documents obtained via experts in the
specialty for English-language articles using the following
search terms in combination: “malaria”, “antimalarials”,
“survey”, “counterfeit drugs”, “substandard drugs”, “falsified”,
“antimalarials”, “artemisinins”, “artesunate”, “drug
resistance”, and “poor quality medicines”. We included only
studies that provided sample numbers, and in which either
chemical assays, packaging analysis, or both, were done on
antimalarial drug samples. We placed no limitations on
survey sampling methods or sources of drugs for inclusion.
for the Thailand–Cambodia border.71 Resistance is
engendered if parasites are exposed to subtherapeutic
blood concentrations of drug, which kill sensitive
parasites while allowing the multiplication and selection
of resistant strains. Tolerance to dihydroartemisinin, the
active metabolite of artesunate, has been induced in vitro
by selection of parasites exposed to different concen-
trations of drugs.72,73
Molecular evidence from parasites suggests that
P falciparum resistance to chloroquine and pyrimeth-
amine came to Africa from southeast Asia.74,75 Research
about the heritability and transmission potential of
parasites resistant to artemisinin suggests that without
successful containment, spread to Africa could occur,
thus heralding a public health disaster.76 Other reasons
for increased reports of poor-quality antimalarial drugs
include the increased number of manufacturers of
artemisinin derivatives without sufficient regulatory
oversight, which further risks proliferation of sub-
standard artemesinin-combination treatments.
No quick solution exists for the issue of poor-quality
antimalarial drugs; rather, a multifaceted approach is
needed to successfully address this global scourge
(panel 3). The Nigerian National Agency for Food and
Drug Administration and Control, the Ghanaian
President’s Malaria Initiative plan, and the Cambodian
Ministry of Health have used several interventions
and innovative approaches to combat poor-quality anti-
malarial drugs. Nigerian81 and Ghanaian programmes
randomly screened drugs in their markets with
Minilabs, and penalised counterfeiters.82 Cambodia’s
programme tackled the falsified drugs at their market
sites through closures of illegal pharmaceutical outlets
and extensive health education campaigns.83 These
findings are a wake-up call demanding a series of
concurrent interventions to better define and eliminate
both criminal production and poor manufacturing of
antimalarial drugs.
494
Contributors
GMLN and JGB designed the study. GMLN did the literature search and
data collection. PNN supported data collection. All authors contributed
to data analysis, interpretation, and writing of the report.
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgments
We thank Stacey Knobler (Fogarty International Center),
Pascal Ringwald (Global Malaria Programme, WHO), and Tom Wellems
(National Institute of Allergy and Infectious Disease) for their advice and
support. PNN is supported by the Wellcome Trust of Great Britain. This
study was funded by the Fogarty International Center, National Institutes
of Health.
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