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

Abstract

Background: Since 1998 the serious public health problem in South East Asia of counterfeit artesunate, containing no or subtherapeutic amounts of the active antimalarial ingredient, has led to deaths from untreated malaria, reduced confidence in this vital drug, large economic losses for the legitimate manufacturers, and concerns that artemisinin resistance might be engendered.

Methods and findings: With evidence of a deteriorating situation, a group of police, criminal analysts, chemists, palynologists, and health workers collaborated to determine the source of these counterfeits under the auspices of the International Criminal Police Organization (INTERPOL) and the Western Pacific World Health Organization Regional Office. A total of 391 samples of genuine and counterfeit artesunate collected in Vietnam (75), Cambodia (48), Lao PDR (115), Myanmar (Burma) (137) and the Thai/Myanmar border (16), were available for analysis. Sixteen different fake hologram types were identified. High-performance liquid chromatography and/or mass spectrometry confirmed that all specimens thought to be counterfeit (195/391, 49.9%) on the basis of packaging contained no or small quantities of artesunate (up to 12 mg per tablet as opposed to approximately 50 mg per genuine tablet). Chemical analysis demonstrated a wide diversity of wrong active ingredients, including banned pharmaceuticals, such as metamizole, and safrole, a carcinogen, and raw material for manufacture of methylenedioxymethamphetamine ('ecstasy'). Evidence from chemical, mineralogical, biological, and packaging analysis suggested that at least some of the counterfeits were manufactured in southeast People's Republic of China. This evidence prompted the Chinese Government to act quickly against the criminal traders with arrests and seizures.

Conclusions: An international multi-disciplinary group obtained evidence that some of the counterfeit artesunate was manufactured in China, and this prompted a criminal investigation. International cross-disciplinary collaborations may be appropriate in the investigation of other serious counterfeit medicine public health problems elsewhere, but strengthening of international collaborations and forensic and drug regulatory authority capacity will be required.

Figure 1. Map of the Distribution of Fake Artesunate, Collected by Wellcome Trust-University of Oxford SE Asian Tropical Medicine Research Programme and Collaborators, in Relation to Packaging Type

Map drawn by Mr. Chongkham Phonekeo.

Figure 2. Examples of Genuine and Counterfeit Holograms

(A) Genuine Guilin Pharmaceutical artesunate blister pack hologram. (B) A type 2 sticker copy. (C) A type 10 hologram copy with the fake ‘X-52′ stamp as seen under UV light. (D) Type 15 hologram copy from the seized counterfeit artesunate from the China/Myanmar border. For a full description of the 16 types of fake packaging see Figure S1 (updated from [10]). Types 15 and 16 have been only recently described and were not included in the pre-seizure analysis presented here. Photographs by Paul Newton.

Figure 3. Plot of δ¹³C and δ¹⁸O Values, in ‰, of Carbonate in Tablets

Also plotted are approximate fields for values expected from calcite in different geological environments; igneous (red), metamorphosed (pink), and unaltered limestone (green). Sample 05/17 is represented by the top right data point.

Figure 4. Photomicrographs of Material Found in Fake Artesunate Tablets

(A) Debris, including charcoal fragments. (B) Pinus pollen grain. (C) Juglans pollen grain. (D) Acacia pollen grain with charcoal deposit. (E) Dermatophagoides mite nymph. The maximum distance across the abdomen is 116 μm. Photographs by Dallas Mildenhall.

Figure 5. Relationship between the Stated Year of Manufacture of Fake Artesunate for Those Bearing Fake Stickers and Fake Holograms in Order of Discovery between 2000 and 2006

Black, found in east and west; yellow, found in easterly distribution only; and blue, found in westerly distribution only.