Review
Poor-quality antimalarial drugs in southeast Asia and sub-Saharan Africa

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Summary

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 We reviewed published and unpublished studies reporting chemical analyses and assessments of packaging of antimalarial drugs.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

3·3 billion people are at risk of malaria, which is endemic in 106 countries. Between 655 000 and 1·2 million people die every year from Plasmodium falciparum infection.1, 2 Much of this morbidity and mortality could be avoided if drugs available to patients were efficacious, high quality, and used correctly. Children in sub-Saharan Africa and southeast Asia have the highest risk of contracting and dying from malaria. The global burden of malaria has reduced in the past decade,3 and endemic countries are reliant on the long-term availability of effective antimalarial drugs to maintain this progress.4

In endemic regions, antimalarial drugs are widely distributed and self-prescribed (incorrectly and correctly) for the many febrile episodes attributed to malaria. Insufficient facilities to check the quality of antimalarial drugs, poor consumer and health-worker knowledge about these drugs, their cost, and the paucity of appropriate regulatory and punitive action makes these drugs attractive targets for counterfeiters.5, 6 Reports of poor-quality antimalarial drugs have increased in the past decade, partly because of growing awareness and concern;6, 7, 8 however, the issue may be much greater than it seems because most cases are probably unreported, reported to the wrong agencies, or kept confidential by pharmaceutical companies.6, 9, 10 Of the many public health consequences of poor-quality antimalarial drugs, drug resistance is a particular concern. Low concentrations of active pharmaceutical ingredient in poor-quality antimalarial drugs can result in subtherapeutic concentrations of drug in vivo, which contributes to the selection of resistant parasites.11, 12 Artemisinin derivatives are the most effective drugs against malaria, and artemisinin-based combination treatments are the recommended first-line treatments for P falciparum malaria.12, 13 Resistance or tolerance to artemisinin derivatives has been described in western Cambodia, and is characterised by slow rates of parasite clearance after treatment.14 Although a causal relation between poor-quality artemisinin derivatives and artemisinin resistance has not been confirmed, modelling analyses suggest that underdosing of patients can play an important part in the spread of resistance.15

Poor-quality antimalarial drugs are very likely to jeopardise the unprecedented progress and investments in control and elimination of malaria made in the past decade. In this Review we assess the issue of poor-quality antimalarial drugs, particularly the artemisinins, emphasise the mechanisms that determine their existence and effect in sub-Saharan Africa and southeast Asia, and describe potential interventions to combat this problem.

Section snippets

Definitions of drug quality

We obtained data for samples in two categories: drugs failing chemical assay analysis and drugs failing package testing; these categories were not mutually exclusive. No universally accepted definitions exist for the different types of poor-quality drugs and national terminologies are diverse. Some nations, and some of those involved in intellectual property law, are concerned that the word counterfeit could wrongly lead to the classification of some legitimate generic drugs as such, thus

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–pyrimethamine, and tetracycline. 1173 samples (82%) were obtained with convenience sampling with no randomisation of outlet selection. All studies used some form of chemical analysis with one or more of the following techniques:

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 treatments, artesunate, chloroquine, mefloquine, quinine, proguanil, and pyrimethamine (table8, 10, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49). 796 (35%) of 2297 samples failed chemical analysis with one or more of the techniques described above for southeast Asia (

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. Antimalarial 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,

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”,

References (83)

  • RD Newman

    Learning to outwit malaria

    Bull World Health Organ

    (2011)
  • R Bate

    Making a killing; the deadly implications of the counterfeit drug trade

    (2008)
  • A Dondorp et al.

    Fake antimalarials in southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials

    Trop Med Int Health

    (2004)
  • P Newton et al.

    Poor quality vital anti-malarials in Africa—an urgent neglected public health priority

    Malar J

    (2011)
  • L Basco

    Molecular epidemiology of malaria in Cameroon. XIX. Quality of antimalarial drugs used for self-medication

    Am J Trop Med Hyg

    (2004)
  • NJ White

    Qinghaosu (artemisinin): the price of success

    Science

    (2008)
  • Essential medicines: regulatory action needed to stop the sale of oral artemisinin based monotherapy

  • GQ Li et al.

    Clinical trials of artemisinin and its derivatives in the treatment of malaria in China

    Trans R Soc Trop Med Hyg

    (1994)
  • AM Dondorp et al.

    Artemisinin resistance in Plasmodium falciparum malaria

    N Engl J Med

    (2009)
  • N White et al.

    Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

    Malar J

    (2009)
  • Preliminary Draft survey of national legislation on counterfeit medicines: feedback from member states to the circular letter CL 25.2009

  • Substandard/spurious/falsely-labelled/falsified/counterfeit medical products

  • PN Newton et al.

    The primacy of public health considerations in defining poor quality medicines

    PLoS Med

    (2011)
  • E Wondemagegnehu

    Counterfeit and substandard drugs in Myanmar and Vietnam

  • Frequently asked questions

  • S Arie

    Contaminated drugs are held responsible for 120 deaths in Pakistan

    BMJ

    (2012)
  • FM Fernandez et al.

    Poor quality drugs: grand challenges in high throughput detection, countrywide sampling, and forensics in developing countries

    Analyst

    (2010)
  • I Abu Reid et al.

    Stability of drugs in tropics. A study in Sudan

    Int Pharm J

    (1990)
  • V Keoluangkhot et al.

    Impaired clinical response in a patient with uncomplicated Falciparum malaria who received poor-quality and underdosed intramuscular artemether

    Am J Trop Med Hyg

    (2008)
  • PN Newton et al.

    A collaborative epidemiological investigation into the criminal fake artesunate trade in South East Asia

    PLoS Med

    (2008)
  • AM Dondorp et al.

    Fake antimalarials in southeast Asia are a major impediment to malaria control: multinational cross-sectional survey on the prevalence of fake antimalarials

    Trop Med Int Health

    (2004)
  • S Sengaloundeth et al.

    A stratified random survey of the proportion of poor quality oral artesunate sold at medicine outlets in the Lao PDR—implications for therapeutic failure and drug resistance

    Malar J

    (2009)
  • United States Pharmacopeia. Fake antimalarials found in Yunnan Province, China....
  • R Bate et al.

    Pilot study of essential drug quality in two major cities in India

    PLoS One

    (2009)
  • JO Okeng et al.

    Chloroquine in the Ugandan market fails quality test: a pharmacovigilance study

    Afr Health Sci

    (2003)
  • A Amin et al.

    The quality of sulfadoxine-pyrimethamine and amodiaquine products in the Kenyan retail sector

    J Clin Pharm Ther

    (2005)
  • G Thoithi et al.

    Drug quality control in Kenya: observation in the drug analysis and research unit during the period 2001–2005

    East Centr Af J Pharm Sci

    (2008)
  • MA Atemnkeng et al.

    Quality control of active ingredients in artemisinin-derivative antimalarials within Kenya and DR Congo

    Trop Med Int Health

    (2007)
  • M Tipke et al.

    Substandard anti-malarial drugs in Burkina Faso

    Malar J

    (2008)
  • Survey of the quality of selected antimalarial medicines circulating in Madagascar, Senegal, and Uganda

  • Survey of the quality of selected antimalarial medicines circulating in six countries of Sub-Saharan Africa

  • Cited by (295)

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