Data for this review were identified by searches of PubMed from 1966 to 2005, with the terms “counterfeit drugs”, “fake drugs”, “substandard drugs”, “counterfeit medicines”, and “fake medicines”. Additionally, E-DRUG (1995–Dec 2005) and SAFMEDICINES (March–Dec 2005) were also searched. Magazine and newspaper articles were searched for with Google and through the help of colleagues in many countries.
ReviewCounterfeit anti-infective drugs
Introduction
Over the past decade, the massive public-health problem of counterfeit and substandard drugs has become increasingly apparent, causing significant morbidity and mortality and reducing the effectiveness of health care in the developing world. There are few accurate estimates of the scale of the problem. Published estimates of the global prevalence of counterfeit drugs range from 1% to 50%.1, 2 Since the pharmaceutical industry produces billions of tablets each year, even 1% of global production would affect millions of people. There is even less objective information on the potential health and economic consequences of poor drug quality and how to stop this lethal trade.
Various countries and organisations use different definitions of counterfeit drugs.3, 4 One of the most widely used is that of the WHO (panel 1), where the emphasis is on the intent to deceive. A counterfeit drug can therefore contain the correct amount of active ingredient, as stated on the label, too much, too little, none at all, or the wrong ingredients. The amount of active ingredient is not sufficient information to determine whether a medicine is counterfeit. This judgment can only confidently be made by the additional inspection of the packaging. In many reports, whether a poor quality medicine is counterfeit or substandard is unclear.6, 7 The distinction between the two categories is vital, since the reasons for their dissemination and potential countermeasures are different.
Counterfeit and substandard medicines have a long history. In the first century in Greece, Dioscorides first classified drugs by their therapeutic use, warned of the dangers of adulterated drugs, and advised on their detection.8 Herbal medicines have a long history of being adulterated; for example, the use of congeners to adulterate Valeriana officinalis root, used for treating cholera,9 and red clay to adulterate the foul-smelling Ferula assa-foetida, which was hung around the neck to ward off infections.10 Since the discovery of potent anti-infectives there have been periodic crises in their quality. In the 17th century, the adulteration of Peruvian Cinchona bark, the first effective treatment of ague (malaria), with other astringent barks and aloes “assumed huge dimensions”.11 This adulteration was precipitated by huge demand for the bark from Europe, where malaria was still endemic. Loss of confidence resulted in a decline in demand, the price plummeted, and the exporting markets were temporarily ruined (figure 1).11, 12
In the UK and USA in the mid-19th century, the widespread adulteration of medicine, especially quinine, prompted the first regulation of the trade in medicines, codes of practice for pharmacists, and guides on the detection of counterfeit drugs.13, 14 In his celebrated screenplay The Third Man, Graham Greene described the hunt for a counterfeit penicillin smuggler in post-war Vienna.15 Although apparently based on a true story,16 recent revelations that his main informant was a Soviet double agent17 cast doubt on whether fake penicillin was in circulation. Counterfeit drugs were first addressed at an international health meeting only 20 years ago and the World Health Assembly adopted a resolution against counterfeit and substandard pharmaceuticals in 1988.8
A search of the medical literature yields only 43 primary published research reports concerning counterfeit drugs, and several reviews.4, 18, 19, 20, 21, 22, 23, 24 Much of the information is only found in the grey literature and newspapers, suggesting substantial under-reporting of the problem in the medical literature. There is almost no information in the public domain on the quality of veterinary medicines and insecticides, which also have an important bearing on human infections. There are reports from Ireland of counterfeit oxfendazole, a domestic mammal anthelmintic,23 and of fake avian influenza vaccine25 and veterinary drugs being repackaged for human use in China.26 Other medicines with adjunctive roles in the treatment of infections are also counterfeited—eg, about 500 children died after ingesting fake paracetamol and cough syrups containing the solvent diethylene glycol, which is a renal toxin.27, 28, 29 Counterfeit diagnostic tests30 and, by recycling, contaminated disposable syringes,31 will also have an important bearing on infections. In India, an estimated 30–50% of used syringes find their way back into shops after washing and wrapping via waste scavengers.31
Numerous factors encourage the counterfeiting of drugs, apart from criminal greed. The relatively high cost of genuine medicines, together with their desirability and shortage, give the counterfeiters an economic incentive, facilitated by lack of legislation and enforcement and light penalties. There is often inadequate liaison between police, customs, and drug regulatory authorities. Lack of knowledge of counterfeits and appropriate preventive measures, together with poor dissemination of information among health workers and the public, make their detection difficult. In the tropics, many patients obtain medicines from untrained vendors without prescription, in inadequate courses, and without information.32 The lack of financial and human resources available to many drug regulatory authorities often makes effective recognition of poor quality drugs and action impossible. Only 20% of WHO member states have well-developed drug regulation and 30% have either no drug regulation or a capacity that hardly functions.4, 5 Corruption is also an integral factor difficult to police, especially when the authorities are involved; for example, the staff of one drug regulatory authority were found to have taken bribes to pass spurious drugs for sale and drug inspectors were reported to charge wholesalers US$65 per month to allow their illegal businesses to continue.33 Complex trade arrangements, without proper documentation, facilitate trade in counterfeits across porous borders, resulting in a low-risk, high-profit venture for counterfeiters.4, 34, 35
Section snippets
The prevalence of counterfeit anti-infectives
A search found references to 206 cases of counterfeit anti-infectives from 38 countries (webtable). Of 771 reports of counterfeit medicines received by WHO between 1982 and 1999, 48·4% were from the Western Pacific region, with most (51·2%) labelled as anti-infectives.3, 36 However, only 5–15% of the 191 WHO member states report cases of counterfeit drug5, 37 and the “scale of the problem…is shrouded in ignorance, confusion and denial”.38 In the absence of objective studies, estimates even for
Content and dissolution properties
The ability to investigate the content of counterfeit or substandard pharmaceuticals is a critical component of monitoring of the drug supply by drug regulatory authorities. Chemical analysis methods such as high performance liquid chromatography (HPLC) and gas chromatography coupled with optical, electrochemical, or mass spectrometric detectors have been the mainstays of pharmaceutical analysis. Gas chromatography has been particularly useful for detecting residual solvents, volatile
Morbidity and mortality
If medicines containing little or no active ingredients, whether counterfeit or substandard, are used for the treatment of common diseases with a high untreated mortality—eg, falciparum malaria, pneumonia, meningitis, typhoid, and tuberculosis—then morbidity and mortality must increase. Despite the innate practical difficulties associated with documenting the effects of drug counterfeiting in remote tropical areas, it has been possible in a few cases to link together a confirmed diagnosis in a
Interventions
There is clearly no simple solution to the problem of counterfeit anti-infectives, but much more could be done now to improve this enormous yet neglected problem that affects particularly the poorest, most vulnerable people. Several interlinked strategies are required, the success of which will depend greatly on increased information sharing and cooperation both within and between countries. A comprehensive, pragmatic plan of action, linking various government organisations, health workers,
Conclusions
That there are, at the very least, large geographic foci with very poor quality medicines circulating for key causes of death and disease is of enormous concern. 14 million people die per year of infectious diseases with more than 90% of these deaths occurring in developing countries. Although Africa and Asia make up 72% of the world's population, they consume only 10·6% of the world drug market.113 If between 10–50% of the drug supply in Asia and Africa is counterfeit, the disparity in the use
Search strategy and selection criteria
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