Fake antimalarials and public health

Paul Newton

Centre for Tropical Medicine, University of Oxford, UK

and

Wellcome Trust-Mahosot Hospital-Oxford Tropical Medicine Research Collaboration, Mahosot Hospital, Lao PDR

Recent Reports of Fake Antimalarials

* Chloroquine* Quinine* Tetracycline/Doxycycline* Sulphadoxine-pyrimethamine * Metakelfin TM

* Mefloquine* Halofantrine* ? Primaquine* Artesunate* Intramuscular and oral artemether* Dihydroartemisinin* Dihydroartemisinin-piperaquine

Not faked ?

* Artemether-lumefantrine

* Atovaquone-proguanil

* iv/im artesunate

Definitions

• Vary between countries and organisations

• WHO definitions:

• Counterfeit “a pharmaceutical product that is deliberately and fraudulently mislabeled with respect to identity and/or source”

• Substandard “a pharmaceutical product with genuine packaging with incorrect quantity of ingredient (not deliberate)”

Fake Cinchona Bark 17th C Europe

Fake Quinine

London 1829

Physicians chastising a drug seller 13th C Arabia

1. Avoidable sickness and death

2. Economic loss to patients & their families, health systems and genuine producers

3. Loss of confidence in key medicines

4. Loss of confidence in health facilities and health staff

5. Burden for drug regulatory authorities

6. Sub-therapeutic amounts of active ingredients - drug resistance

7. Unexpected adverse effects from harmful ‘wrong’ ingredients

CONSEQUENCES of FAKE DRUGS

Artesunate • Developed in China• Vital antimalarial in SE Asia• Without which we may have

malaria that cannot be treated at a an affordable cost

Fake artesunate in mainland SE Asia • 2000-2001 38 % of shop bought artesunate

was counterfeit, containing no active drug

• One NGO bought 100,000 tablets in one shop

• 2002-2003 53% of shop bought artesunate

was counterfeit

There are ~ 2 x 106 cases of P. falciparum /year in WPRO - in ‘untreated’ non-immunes the excess mortality will be considerable

Genuine Hologram Fake Artesunate ‘Type 8’

Genuine Hologram Fake Artesunate ‘Type 10’

Traces of artesunate

• Recent samples from the Thai/Burma border contain 3-10 mg artesunate per tablet (genuine tablet ~ 50mg artesunate)

• May engender artemisinin resistance - which has started to appear on Thai/Cambodian border

Fake artesunate ‘wrong’ ingredients• Paracetamol• Sulphadoxine• Pyrimethamine• Dimethylfumarate• Erythromycin A-F & anhydroerythromycin• Erucamide• Safrole• Artemisinin• Metamizole • Chloramphenicol• Metronidazole• Chloroquine• Sulphamethoxazole

An under appreciated Asian public

health disaster

* Malaria remains a problem in SE Asia, but we have the tools for control

* Counterfeit artesunate MUST be a major risk for death and an impediment to malaria control

* Despite 6 years of awareness - situation deteriorating and little action despite severe danger to public health

* How many additional deaths - thousands ?

INTERPOL/WPRO Investigation

• Northern temperate pollen with plants like firs, pines, cypresses, sycamores, alders, worm wood, willows, elms, and numerous fern spores present

• Flora suggests possible source in southern China near the mountains bordering Burma and/or northernmost Viet Nam

Debris, including Juglans pollen

charcoal fragments

Dermatophagoides mite nymph

Valid batch numbers, stickers, multiple wrong

AIs, calcite

Invalid batch numbers, holograms, subtherapeutic artesunate

• INTERPOL presented the evidence to the Ministry of Public Security, People’s Republic of China - who acted very quickly with a criminal investigation and arrests

• Seized 24,000 of 240,000 blisterpacks traded by those arrested

• Enough to allow 240,000 adults to die

WANTEDWANTED

Genuine Hologram Fake Artesunate ‘Type 15’

Similar to Type 10 - found only in N Burma and N Laos (Westerly trade route)

Fake artemisinin derivatives in Africa

• Enormous effort has been invested in determining optimum therapy for diseases such as malaria

• Many worthwhile competing public health priorities…but…

• Little point in doing clinical trials if insufficient effort is invested in ensuring that the drugs used in clinical practice are of good quality

What can be done ?• Support for the drug regulatory authorities…

without effective DRAs most interventions cannot work

• Building of sustainable links between country DRAs, police, forensic scientists, criminal analysts, WHO and INTERPOL

• Research on prevalence of poor quality drugs and efficacy of interventions

What can be done ?

• Education of health workers and patients

• Provision of inexpensive, available key antimalarial drugs - undercut the counterfeiters

• • Remove artemisinin derivative

monotherapies as free accessible ACTs become available

• Political will to tackle these problems

AcknowledgementsThe laboratories and their staff

The Government of the People’s Republic of China

Food and Drug Quality Control Centre & Food & Drug Department, Lao PDR

Guilin Pharmaceutical Co. Ltd, China

The Natural History Museum, London and Wolfson College, Oxford, UK

David Pizzanelli, Mayfong Mayxay, Bryan Watt, Arjen Dondorp, Frank Smithuis, François Nosten, Lucy Paiphun, Aung Pyae Phyo, Khin Mg Lwin,

Rose McGready, Shunmay Yeung, Chongkham Phonekeo, Christopher Curtis, Sue Lee, Nicholas Day, Nicholas White and anonymous collectors for their help

and advice

Funded by Wellcome Trust of Great Britain, the participating institutions and the

United States Agency for International Development through US Pharmacopeia

Facundo M Fernández, Aline Plançon, Dallas C Mildenhall, Michael D Green, Li Ziyong, Eva Maria Christophel,

Souly Phanouvong, Stephen Howells, Eric McIntosh, Paul Laurin, Nancy Blum, Christina Y Hampton, Kevin Faure,

Leonard Nyadong, CWR Soong, Budiono Santoso, Wang Zhiguang, John Newton, Kevin Palmer

Centre for Tropical Medicine, Churchill Hospital, University of Oxford, UKSchool of Chemistry & Biochemistry, Georgia Institute of Technology, USA

Intellectual Property Crime Unit, INTERPOL, FranceGNS Science, New Zealand

Division of Parasitic Diseases, CDC, USAIntellectual Property Division, Ministry of Public Security, Beijing, People’s

Republic of ChinaWestern Pacific Regional Office of the World Health Organization, The

PhilippinesUnited States Pharmacopeia, USA

Therapeutic Goods Administration, Australia, Royal Canadian Mounted Police, Forensic Laboratory Services, Canada