Microsoft word - 481f139c-44e2-28f83e.doc

Embargoed: May 6, 2008 8:00pm EST

Antimalarial Drug Quality in the Most Severely Malarious Parts of Africa – A Six Country
Study

Roger Bate1,2, Philip Coticelli1*, Richard Tren1, Amir Attaran3
1 Africa Fighting Malaria, Washington, D.C., United States of America,
2 American Enterprise Institute, Washington, D.C., United States of America,
3 Institute of Population Health & Faculties of Law and Medicine, University of Ottawa, Ottawa,
Canada

* E-mail: pcoticelli@fightingmalaria.org
Abstract

A range of antimalarial drugs were procured from private pharmacies in urban and peri-urban
areas in major cities of six African countries, situated in the part of that continent and the world
that is most highly endemic for malaria. Semi-quantitative thin-layer chromatography (TLC)
and dissolution testing were used to measure active pharmaceutical ingredient content against
internationally acceptable standards. 35% of all samples tested failed either or both tests, and
were substandard. Further, 33% of treatments collected were artemisinin monotherapies, most of
which (78%) were manufactured in disobservance of an appeal by the World Health
Organisation (WHO) to withdraw these clinically inappropriate medicines from the market. The
high persistence of substandard drugs and clinically inappropriate artemisinin monotherapies in
the private sector risks patient safety and, through drug resistance, places the future of malaria
treatment at risk globally.

Introduction
Malaria surged in sub-Saharan Africa in the 1990s, due in part to increased resistance to
chloroquine and sulfadoxine-pyrimethamine (SP).[1] Exposure to substandard antimalarial
drugs likely exacerbated this trend.[2,3,4] Pressure from malaria scientists prompted wholesale
adoption of artemisinin-based combination therapies (ACTs) by endemic country governments
and donors.[5] In January 2006, the WHO issued new treatment guidelines for the first time in
20 years recommending ACTs for the treatment of uncomplicated malaria. The WHO further
called to end the production and marketing of artemisinin monotherapies in order to protect these
formulations against parasitic resistance. According to the WHO’s antimalarial drug quality
database, every national treatment policy in sub-Saharan Africa except Swaziland and Cape
Verde now recommends treating uncomplicated malaria with ACTs.
These well-intentioned changes might remain unrealized and vulnerable. Substandard ACTs,
and “legitimate” artemisinin monotherapies, are unparalleled threats driving clinical failure of
malaria treatment.[6,7,8] Especially in Sub-Saharan Africa, governments lack the ability
through customs and policing to stop these medicines entering the private market, where many
(oftentimes most) persons buy their treatment.[9,10] Unless these medicines are of a
consistently high quality, the great strides made in recent years to transition from chloroquine
and SP to ACTs could be imperiled by drug resistance. This study is the first to sample the
quality of medicines throughout the geographic band of hyper- and holoendemic P. falciparum
malaria which stretches unbroken from West, to Central, to East Africa—the world’s worst.[11]

Results

195 treatment packs were tested, producing 210 sample results. The difference between tests and
results is explained in that co-packaged, but not co-formulated ACTs, such as artesunate and
amodiaquine were tested as individual monotherapies.
Overall 35% (73/210) of tested samples were substandard and failed either TLC or dissolution
tests (See Table 1). Of the specific pharmaceutical types, failure by TLC, dissolution or both,
occurred in 38% of SP, 48% of amodiaquine, 24% of mefloquine, 31% of artesunate, 27% of
artemether, 55% of dihydroartemisinin and 19% of artemether-lumefantrine fixed-dose
combinations.
Artemisinin monotherapy, which the WHO rejects as inherently substandard treatment even
when its dosage is correct, remains common in Africa. 33% (64/195) of all treatment packs
tested were artemisinin monotherapies, and 42% (27/64) failed either TLC or dissolution tests.
78% (50/64) were manufactured after the WHO’s January 2006 appeal to halt monotherapy
production. A further sign that certain manufacturers of artemisinin monotherapies do not take
clinical efficacy seriously was the tremendous heterogeneity in expiry dates: 10 listed an
expiration date of two years, while most (42/64) listed three years. Five listed an expiration date
of four years, and seven lacked either a manufacture date or both a manufacture date and
expiration date. Names of the offending artemisinin monotherapy producers in this study were
forwarded to the WHO.
The authors did not attempt a forensic examination of trademarks or product designs to
differentiate between products that were merely substandard and those which were deliberately
counterfeited, as neither is clinically suitable. However, there was an apparent trend in that
failing products more often originated or were claimed to originate from poorer parts of the
world with weaker regulatory systems: failure rates were 48% (30/63) for Africa, 32% (29/90)
for Asia and 24% (12/50) for Europe (See Table 2). Only four US-manufactured samples were
tested; none failed.
Discussion
This study sheds light on the availability and relative quality of private sector antimalarials in Africa’s private sector. In countries situated in the world’s most intense region of holoendemic and hyperendemic P. falciparum malaria, where the difference between a proper and a bogus medicine cannot be surpassed, various substandard therapies and clinically inappropriate monotherapies remain widely available, with between a quarter and over half of products sold in urban and peri-urban pharmacies failing basic quality testing. We do not quantitatively estimate the public health impact of this crisis, but it must be staggering. The WHO has taken diplomatic steps to fight this problem. It coordinates a passive reporting system for substandard medicines, for example, and World Health Assembly Resolution WHA60.18 of May 2007 committed member states to cease production and marketing of
artemisinin monotherapies. Our study results suggest these diplomatic efforts alone are not
making a sufficient impact in the field. To be effective, the WHO needs its partners to support
policy change, which we describe here.
Other international agencies must apply leverage, apart from the WHO’s sole diplomatic efforts.
Major financiers of malaria treatment, such as the Global Fund and the World Bank, should
make aid conditional on countries de-listing oral artemisinin monotherapies from national
formularies. The World Trade Organisation, which sets the rules of global commerce, should
enact rules prohibiting the international trade in artemisinin monotherapies and reducing the
tariffs on proper medicines to zero. These steps will ensure that less money flows to the
inappropriate monotherapies, and that ACTs are made less expensive. The political traction to
accomplish these steps should come from the Group of Eight leading industrial countries, who
declared ACTs a global priority in 2005.
Effort must also be made to reverse the various initiatives which now spend public money on
inadequately regulated medicines. The Global Fund, for example, finances the purchase of
medicines whose quality is not approved by the WHO’s prequalification scheme or any
developed country’s regulatory authority – known as “Option C” medicines. According to an
internal report published by the Wall Street Journal, the World Bank recently discovered in an
audit that malaria medicines it purchased in India from a local manufacturer were clinically
substandard.
These incidents argue strongly for a rule against purchasing locally-manufactured medicines,
except where those medicines have received regulatory approval from a developed country or the
WHO’s prequalification scheme. The WHO’s current practice, which regards a medicine as good
enough if it has applied for prequalification, but not necessarily passed the WHO quality
standards and received prequalification, is an unprincipled distortion of the rules. Similarly
stringent rules must inure to the proposed $1.9 billion Affordable Medicines Facility for malaria,
which intends to provide clinically effective ACTs at retail outlets where they are needed.
Unless this initiative employs standards higher than the current Global Fund and World Bank
ones and strengthens post-market surveillance, it risks to expand the supply of the substandard
and inappropriate treatments found in this study, which would be disastrous in clinical and drug
resistance terms both.[13]
Further, this study demonstrates that at the local level, the capacity for basic drug quality tests to
strengthen post-market surveillance can be deployed with relative ease. A Minilab® or
equivalent technology costs about $4,000, requires modest training, and can be run in an
ordinary air-conditioned room. The marginal cost to test 10 samples out of 10,000 (for a
sampling ratio of 0.1%) is about $2, and can be completed in under an hour. Training programs
for district level malaria officers and regulatory officials in Southeast Asia could be replicated in
sub-Saharan Africa.[14] Such simple and cheap technology should be distributed more widely,
to the ministry of health, police, customs services and non-governmental organizations. A
decentralized effort of this kind, with drug quality watchdogs at several layers of government
and in civil society, could be effectively tried in a country for only tens of thousands of dollars.

Materials and Methods

A simple sampling protocol was developed in line with similar studies.[12] Antimalarial drugs
were obtained by local nationals from randomly selected private pharmacies in major cities of six
African countries within the high endemicity band. Study agents posed as customers were asked
to purchase a sample lot of antimalarial tablet formulations available, namely: SP, amodiaquine,
mefloquine, artemisinin monotherapies and any ACTs. Agents were instructed not to purchase
chloroquine. Treatment packs were maintained either in the manufacturer’s original packaging
or loose, and stored at ambient temperature until testing. Tests were completed within 40 days of
sample collection.
The Global Pharma Health Fund e.V. Minilab® was used to run semi-quantitative thin-layer
chromatography (TLC) and dissolution tests on each sample to determine the presence and
relative concentration of active ingredients. Each test was run in duplicate, with the generous
assumption that the result more consistent with the reference was recorded. The Minilab®
protocols award products a “pass” if they have 80% or more of the labeled active ingredient(s)
(note there is no upper-bound limit). For fixed-dose combinations and SP, “pass” was awarded
only if both active ingredients met this standard.
Acknowledgments
The authors would like to thank Kimberly Hess for her analysis of study data, as well as Carlos
Odora, Franklin Cudjoe, Thompson Ayodele, Greg Starbird and Aime Mutembe for their
invaluable help in the collection of drugs studied.

References

1 Gomes M, Wayling S, Pang L (1998) Interventions to improve the use of antimalarials in
south-east Asia: an overview. Bull World Health Organ 76(1): 9-19.
2 Minzi OMS, Moshi MJ, Hipolite D, Massele AY, Tomson G, et al. (2003) Evaluation of the
quality of amodiaquine and sulphadoxineÚpyrimethamine tablets sold by private wholesale
pharmacies in Dar Es Salaam Tanzania. Journal of Clinical Pharmacy and Therapeutics 28: 117–
122.
3 Amin AA, Snow, RW, Kokwaro GO (2005) The quality of sulphadoxine-pyrimethamine and
amodiaquine products in the Kenyan retail sector. Journal of Clinical Pharmacy and Therapeutics
30: 559–565.
4 Basco LK (2004) Molecular epidemiology of malaria in Cameroon. XIX. Quality of
antimalarial drugs used for self-medication. Am J Trop Med Hyg 70(3): 245-250.
5 Attaran A, Barnes KI, Curtis C, D'Alessandro U, Fanello CI, et al. (2004) WHO, the Global
Fund and medical malpractice in malaria treatment. The Lancet 363(9404): 237-240.
6 Dondorp AM, Newton PN, Mayxay M, Van Damme W, Smithuis FM et al. (2004) Fake
antimalarials in Southeast Asia are a major impediment to malaria control: multinational
crosssectional survey on the prevalence of fake antimalarials. Trop Med Int Health 9(12):1241-6.
7 Hall KA, Newton PN, Green MD, De Veij M, Vandenabeele P et al. (2006) Characterization of
counterfeit artesunate antimalarial tablets from southeast Asia. Am J Trop Med Hyg 75(5): 804-
811.
8 Newton PN, McGready R, Fernandez F, Green MD, Sunjio M, et al. (2006) Manslaughter by
Fake Artesunate in Asia—Will Africa Be Next? PLoS Med 3(6): e197
doi:10.1371/journal.pmed.0030197
9 Snow RW, Peshu N, Forster D, Mwenesi H, Marsh K (1992) The role of shops in the treatment
and prevention of childhood malaria on the coast of Kenya. Trans R Soc Trop Med Hyg 86(3):
237-239.
10 Goodman C, Brieger B, Unwin A, Mills A, Meek S et al. (2007) Medicine Sellers and
Malaria Treatment in Sub-Saharan Africa: What Do They Do and How Can Their Practice Be
Improved? Am J Trop Med Hyg 77(6): 203-218.
11 Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005) The global distribution of
clinical episodes of Plasmodium falciparum malaria. Nature 434(7030): 214-217.
12 Lon CT, Tsuyuoka R, Phanouvong S, Nivanna N, Socheat D, et al. (2006) Counterfeit and
substandard antimalarial drugs in Cambodia. Transactions of the Royal Society of Tropical
Medicine and Hygiene 100: 1019-1024.
13 Green MD (2006) Antimalarial drug resistance and the importance of drug quality
monitoring. J Postgrad Med 52(4): 288-90.
14 Vijaykadga S, Cholpol S, Sitthimongkol S, Pawaphutanan A, Pinyoratanachot A, et al. (2006)
Strengthening of national capacity in implementation of antimalarial drug quality assurance in
Thailand. Southeast Asian J Trop Med Public Health 37(3): 5-10.
Tables

Table 1: Testing results by formulation and country purchased for TLC and dissolutioni,ii
38% (19/50)
48% (14/29)
24% (4/17)
31% (15/49)
27% (3/11)
55% (12/22)
19% (6/32)
35% (13/37)
38% (16/42) 32% (7/22)
33% (3/9) 32% (11/34) 35% (23/66) 35% (73/210)
i. Percentages are supported by (total that failed either dissolution or TLC/total treatments tested)
ii. Co-packaged ACTs are listed as individual monotherapies
Table 2: Testing results by region of manufactureiii
Region of
iii. Manufacturer information not available for 3 tested samples

Source: http://fightingmalaria.org/pdfs/plosantimalarialdrugstudy.pdf