JAC Advance Access originally published online on June 5, 2007
Journal of Antimicrobial Chemotherapy 2007 60(2):214-236; doi:10.1093/jac/dkm109
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Reviews |
Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence
1 Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece 2 Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
* Correspondence address. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece. Tel: +30-694-611-0000; Fax: +30-210-683-9605; E-mail: m.falagas{at}aibs.gr
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Abstract |
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Top
Abstract
IntroductionThere is growing universal concern regarding counterfeit medications. In particular, counterfeit antimicrobial drugs are a threat to public health with many devastating consequences for patients; increased mortality and morbidity and emergence of drug resistance. In addition, physicians treating these patients lose their confidence in the medications used and report high levels of bacterial resistance. The problem with fake and suboptimal medications got worse with the advent of the World Wide Web; a significant proportion of medications that are sold through Internet pharmacies is counterfeit. Various initiatives of the WHO (the International Medical Products Anti-Counterfeiting Taskforce) are hopefully going to tackle this very important public health issue. In this article, we review the available evidence in peer-reviewed articles and World Wide Web information resources regarding the issue of counterfeit antimicrobials.
Keywords: low-quality antimicrobials , quality testing , fake antimicrobial agents
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Introduction |
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Drug quality is currently receiving renewed international attention.1 Over the past decade, there has been an increase in public awareness of the existence of counterfeit and substandard drugs,2–5 which have been increasingly reported in developing countries where drug regulations are ineffective.6–14 Although practically all types of pharmaceutical products have been shown to be involved, the existing data suggest that anti-infectious agents, particularly antibiotics and antiparasitic agents, are the most counterfeited products in developing countries.1,15,16
To implement effective countermeasures against counterfeit and substandard drugs, there is a need for more data to define the extent of the problem. The issue of poor quality drugs has been discussed more in the mass media including newspapers than in the biomedical literature. Many reports that this topic are however anecdotal, which makes quantitative assessment difficult.10,17 Few studies have been reported that systematically examine drug quality,7–12 and have investigated poor quality drugs in terms of correct amount of active ingredient present. More specifically, although drugs that treat serious diseases such as malaria, tuberculosis, AIDS or other infections are more often the object of counterfeits,18,19 there have been scarce reports that systematically review data of low-quality antimicrobials. Therefore, we performed a review of the available scientific evidence on counterfeit and/or substandard antimicrobial drugs. More specifically, we set out to explore the causes and prevalence of this problem and summarize the categories of antimicrobials that have been reported to be counterfeit or substandard. We then discuss the characteristics of these low-quality antimicrobials, their consequences to patients and in our society and finally what interventions have been put into place to cope with this menace.
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Literature review |
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Two reviewers (T. K. and I. K.) independently performed the literature search, study selection and data extraction. The following terms were used in searches of the PubMed database (1966–2006): ‘counterfeit drugs’, ‘substandard drugs’, ‘fake drugs’, ‘substandard antimicrobial agents’, ‘fake antimicrobial agents’, ‘counterfeit antimicrobial agents’, ‘substandard antibiotics’, ‘fake antibiotics’ and ‘counterfeit antibiotics’. Magazine and newspaper articles were searched for with Google and we screened articles related to the initially identified publications to expand our data sources.
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Definitions |
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The subject of overall drug quality has been addressed in several WHO publications.20–22 Substandard drugs are genuine products that have not passed the quality testing protocols previously set for each product.23 The testing protocols and specifications are published in official pharmacopoeias such as the United States Pharmacopoeia (USP), the European Pharmacopoeia and the WHO International Pharmacopoeia. In addition, many countries have published their own pharmacopoeias. More specifically, substandard drugs have incorrect quantity of active ingredient, which could be secondary to excessive decomposition of active ingredient as a result of high temperature and humidity, and poor quality assurance during the manufacture of pharmaceutical products in less-developed countries.
One special class of substandard drugs is the class of counterfeit drugs. Several countries have their own definitions as to what constitutes a counterfeit drug and there is no consensus. This poses a problem in that what may be considered a counterfeit product in one country will not necessarily be so in another country. The WHO has defined counterfeit drugs as those that are deliberately and fraudulently mislabelled with respect to identity and/or source.24 Counterfeit products include drugs with the correct ingredients or with the wrong ingredients, without active ingredients, with insufficient active ingredient or with fake packaging.25 According to a WHO report, analysis of the content of a drug preparation cannot therefore determine whether or not the sample is counterfeit, because the inclusion of inappropriate quantities of active ingredient during manufacture cannot be identified as deliberate.15
Using the above definitions, the variations in active ingredient and weight above or below the recognized limits found in different studies in the current report point to problems in good manufacturing practice, deliberate counterfeiting or poor retail management. Although it is very important to make a clear distinction between the various terms for poor quality medications such as ‘counterfeit’, ‘fake’ or ‘substandard’ drugs in the majority of reports reviewed herein, it was not clarified whether the substandard drug was counterfeit or simply the result of a defect in the manufacturing process.7,12 Thus, although these two terms are indicative of different problems that must be addressed using different strategies, we use the term ‘counterfeit/substandard’ drug, whenever the cause of the poor quality medication is not clear.
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Causes of poor quality drugs |
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The poor quality of drugs has been linked to counterfeiting of medicines,26 chemical instability especially in tropical climates,27 and poor quality control during manufacture.28 Many factors contribute to the increased prevalence of substandard and counterfeit medications. Much of the counterfeit drug trade is probably linked to organized crime, corruption, the narcotics trade, the business interests of unscrupulous politicians and unregulated pharmaceutical companies.29,30 According to the WHO guidelines, factors that influence the prevalence of counterfeit drugs in any particular country include weak or absent drug regulatory authority, absence of a legal mandate for licensing of manufacture/import of drugs, lack of regulation by exporters and within free trade zones, proliferation of small pharmaceutical industries, complex transactions involving many intermediaries, high demand for curative and preventive drugs and vaccines exceeding supply, high prices and inefficient cooperation among stakeholders.1 The WHO Essential Drug Program has failed in most countries31 because of personal financial interests at local, national and foreign levels or a black market. Studies indicate that a country's capacity to restrict dangerous drugs depends heavily on its wealth.9 It is surprising that almost a third of WHO member countries have poor means of controlling counterfeit medications.30 In these circumstances, the market for counterfeit and substandard drugs becomes a lucrative one. In addition, lack of good manufacturing practices (GMP) is common in local pharmaceutical industries in most developing countries because of many hurdles such as frequent power cuts and shortage of water.9 In addition to the existence of substandard drugs, assurance of the stability of pharmaceuticals marketed in developing countries (most of which have tropical climates) is a challenging issue as poor storage conditions, high temperature and high humidity conditions generally enhance chemical degradation and may alter the biopharmaceutical properties of the drugs,32,33 as it has been shown for antibiotics such as tetracyclines.34 Finally, medicine sellers often exhibit lack of concern about expiration dates and storage conditions, especially in poor settings and in the absence of national control, and this can increase the spread of substandard antimicrobials.35,36 Manufacture of generic versions of patented drugs for humanitarian reasons may also be abused in developing countries.37
In contrast, in developed countries such as the USA, other factors contribute to the spread of counterfeit medicines. For example, it is well known that underinsured or uninsured individuals and some states and local governments are turning to the Internet and foreign pharmacies, particularly what they believe to be safe, reputable Canadian pharmacies, to find less costly medications. However, Internet pharmacies, even licensed ones in Canada, are increasingly buying from foreign sources themselves to meet American demand38 and thus import of counterfeit and substandard medications may be enhanced. Finally, certain antimicrobials such as artemisin derivatives are not only confined to Asia and Africa but also to other countries of the industrialized world as they have a natural plant origin and tourists commonly buy them in the tropics as a standby treatment and they are also readily available on the Internet.39
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Prevalence of counterfeit and substandard antimicrobials |
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The magnitude of the drug-counterfeiting problem is considerable and is difficult to gauge as any true estimate of prevalence is difficult. The WHO estimates that up to 10% of the world's pharmaceutical trade—25% in developing countries—consists of fakes,18,40 whereas up to 25% of all drugs consumed in poor countries are thought to be counterfeit or substandard, according to the figures from the US Food and Drug Administration (FDA).41 Many studies have tried to provide estimates of prevalence of counterfeit/substandard antimicrobials [Table S1, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)].
A search of the medical literature yields a limited number of primary published research reports concerning counterfeit drugs and much of the information is only found in the grey literature and newspapers. Few published studies describing the prevalence of counterfeit anti-infectives provided sufficient methodological details to interpret the results6,7,11,12,14,36,42–59 and to control for potential bias or other factors such as instability of some medicines,42 whereas only in very few studies, there was random sampling with adequate description of methods.7 In the current review, we analyse the major studies that have been published regarding counterfeit/substandard antimicrobials (Tables 1 and 2) and also describe the separate categories of these antimicrobials, which include antibiotics, antiviral and antiparasitic agents and vaccines.
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Categories of poor quality antimicrobials |
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There have been reports of substandard/counterfeit drugs in almost all categories of antimicrobials including antibiotics and drugs used to treat tuberculosis, malaria and HIV/AIDS. In the developing world, antibiotics and antiparasitic agents, the drugs that are most needed there, are the counterfeiters' favourites. Other pharmacotherapeutic groups were represented in almost equal frequencies.60 There are 8–10 times more reports for counterfeit antibiotics and 2–3 times more reports for antiparasitic drugs in comparison with other counterfeit drugs.60
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Antibacterial agents |
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A wide range of antibacterial agents have been found to be substandard or fake (Tables 1 and 2). Although no part of the world is exempted, southeast Asia and Africa seem to be particularly plagued by counterfeited antibacterial agents. Especially ‘old’ antibiotics, such as penicillin, tetracycline, trimethoprim–sulfamethoxazole and chloramphenicol, are among the favoured counterfeited antimicrobials.6
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Antituberculosis (anti-TB) drugs |
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A substantial number of anti-TB drugs from several countries, particularly fixed-dose combinations, were found to be substandard [Table S2, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. In contrast, some other studies have shown good quality of anti-TB drugs.61–63
In contrast to other medications, anti-TB drugs are stable under storage conditions, so substandard levels are usually not caused by instability.61,64 Specific, robust and simple colorimetric methods such as thin-layer chromatography (TLC) can be used for the detection of substandard TB medications, especially in many Third World countries with relatively modest laboratory facilities63 where resources such as HPLC are not available or routine use is impractical.65 These substandard anti-TB medications can lead to emergence of drug resistance. Patients receiving a lower therapeutic dose than would be required for their treatment due to a substandard anti-TB drug could lead to drug resistance and treatment failure, despite 100% adherence to the treatment regimen by patients.65,66
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Antiviral agents |
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Counterfeit antiviral agents such as oseltamivir and interferon and antiretroviral agents have been reported [Table S3, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. Most of these reports, however, are anecdotal. More specifically, the recent report of substandard/counterfeit antiretroviral agents either alone or in combinations is very alarming [Table S3, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. On the other hand, in one study, drug content among generic antiretroviral preparations containing the non-nucleoside reverse transcriptase inhibitor nevirapine has been studied, and no substandard preparations were identified.51 Importantly, the recent discovery of counterfeit antiretrovirals raises the prospect of a disastrous setback in the treatment of AIDS in areas such as sub-Saharan Africa, unless vigorous action is taken now.
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Antiparasitic agents |
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Antimalarials
The quality of antimalarial drugs is especially crucial, given the widespread nature of the disease and its importance to global public health.67 As more than 40% of the world's population is at risk of malaria, antimalarial drugs have become a favourite target of counterfeiters. In the last years, many articles reported examples of counterfeit and substandard antimalarial medicines in developing countries (Tables 3 and 4). In a WHO survey of seven African countries, 20% to 90% of antimalarial drugs failed quality testing.68 Many studies have reported that a considerable proportion of antimalarial drugs obtained from east African countries is of poor quality7,12,17,69 and that even counterfeits of new antimalarial drugs, such as artesunate and mefloquine, are circulating in southeast Asia.14,70,71 Counterfeit artemisinins are a significant problem in southeast Asia14,55,72 and are expected to become a serious problem in Africa where artemisinin combination therapy is being implemented.39 The problem of antimalarial drug resistance as a result of counterfeit drugs has been addressed in recent reports.73 Considering the importance of antimalarial treatment in the tropical developing countries, where malaria is endemic and is the first cause of death for children, the presence of counterfeit and substandard drugs on the pharmaceutical market is a risk to the life of millions of people.
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Other antiparasitic drugs
Except for antimalarial drugs, there are reports for substandard anthelmintics and other antiparasitic agents such as pentavalent antimonials [Table S4, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)], which contribute to poor compliance, therapeutic failure and the appearance of resistance in parasites.74
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Other antimicrobial agents |
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Substandard/counterfeit antifungal agents such as griseofulvin and nystatin have been reported in Sierra Leone75 and Ukraine,76 respectively. In addition, there have been reports about substandard antiseptics such as betadine.77 Finally, substandard/counterfeit vaccines have been reported [Table S4, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)] and according to a study, only 3 of 10 vaccine-producing countries in the Asia-Pacific region were assessed to have internationally acceptable standards for vaccine production and quality control and effective regulatory mechanisms.78
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Characteristics of substandard/counterfeit drugs |
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Counterfeit drug products come in many variations. Some do not contain any of the active (pharmaceutical) ingredients (AI) or include the ingredient in harmful amounts. Other preparations come from an unacceptable source or are differently formulated, may contain unacceptably high levels of impurities or impurities such as mould or packaging that falsifies the product's true expiration date, whereas others contain a completely different active ingredient.
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Inappropriate packaging |
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Fake pharmaceuticals often have the same appearance as the brand name and generic drugs they mimic. They are generally indistinguishable in their outward packaging, and pill colour, shape, size and markings; they even have electronic bar codes, which pharmacists scan to verify drug authenticity.79 In developing countries, many of the purchased drugs without packaging were counterfeit.53 Examples of antimicrobials with false packaging and labelling include antibiotics such as penicillin,48 chloramphenicol,6 tetracyclines,6,36,54,57,80 co-trimoxazole,58 quinolones36 and aminoglycosides75,81 and antimalarials such as chloroquine,53 mefloquine,59 quinine82 and artesunate.14,44,61,70
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Reduced stability and bioavailability |
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Several studies that have reported on the stability of essential drugs under real storage conditions in the tropics27,33,83,84 in warehouses and in some wholesale pharmacies may not be satisfactory for ensuring the integrity of drug products.85–87 Antibiotics in particular, e.g. ampicillin,88 may degrade during transportation or storage at temperatures above 25°C and high humidity.33 Other drugs, however, may be stable under such conditions83 and there are studies that have shown that high storage temperatures do not affect adversely the content of many antibiotics including penicillins and tetracyclines12,83 and this may suggest that the most likely cause of low quality is to be found during manufacturing.48
Moreover, interactions may occur when products are stored at high temperature and humidity, consequently reducing the dissolution rate.85 Although many substandard antimicrobials may contain the appropriate amount of active ingredient, they can have suboptimal activity and this may be due to reduced bioavailability. Examples include tetracyclines,34 co-trimoxazole,32 metronidazole,32 pyrimethamine,50,89,90 chloroquine91 and mefloquine.59
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Reduced concentration of active ingredient |
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Low concentration of active ingredient in antimicrobials may be the result of poor manufacturing or could be the effect of poor transport and storage conditions and often it is not possible to distinguish between these two causes (Tables 2 and 4). Decomposition was the cause of poor quality in a number of samples,7,88 but as it has been shown that many antibiotics may be stable even under tropical conditions,83 overall poor manufacturing appeared to be the prevalent cause of low quality.7,48 However, the effect of storage conditions on drug quality has not been assessed in all studies.42 Finally, reduced concentration of active ingredient could also be the result of dilution of drugs with other substances such as contaminated water29,79 or sugar.92
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Altered chemical content |
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Additionally, counterfeit drugs may be characterized by altered odour because they contain diluted active ingredients, or in many cases harmful additives. Sometimes, the counterfeit drugs are chemically identical to the real product, making them counterfeit generics; however, most fakes contain inactive or harmful ingredients. The capsules or tablets may contain, for example, a wrong antibiotic such as erythromycin,39 or they may contain only worthless flour, starch or powder.29,39,93,94 Notorious recent real examples include neomycin eye drops and meningococcal vaccine made of tap water, ampicillin consisting of turmeric and antimalarials and antibiotics containing no active ingredients.14,26,71,95
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Methods for the detection of counterfeit/substandard antimicrobials |
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Several methods have been used for the detection of substandard medications including inspection, dissolution assays, colorimetric methods and chromatography techniques such as HPLC, TLC, Mini-lab and mass spectrometry [Table S5, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/)]. Visual control, dissociating tests or simple colour reaction tests reveal only very rough forgeries. Fast, easy, reliable and non-expensive methods of drug screening are essential, especially in developing countries in the setting of lack of systematic control of the pharmaceutical market and the absence of specific regulations. Finally, new technologies such as near infrared spectroscopy96 and X-ray powder diffraction method97 have been increasingly used for the detection of counterfeit antimicrobials.
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Consequences of counterfeit and substandard anti-infectives |
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The use of low-quality drugs can result in adverse clinical outcomes such as lack of effect and treatment failure, risk of development of bacterial resistance, toxicity or side effects,14,42,66 all of which contribute to the burden of disease and consequently to excess mortality and morbidity.3 However, to the best of our knowledge, there are no reports (e.g. cohorts) that have studied these consequences of low-quality drugs in a systematic approach using adequate scientific methodology. The potential risk of counterfeit anti-infectious agents for individual and community health includes clinical aggravation leading to complications and even mortality from either the disease itself or possible toxic components in the product and selection of drug-resistant bacteria and parasites. These risks have been described on the basis of cases, case series or even epidemics in one case.98
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Consequences for the patients |
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Counterfeit and substandard medicines could also cause adverse effects such as allergic or other side effects through excessive dose or due to the presence of potentially toxic active ingredients53 or pathogenic contaminants,99 as has been reported for some antimicrobials including antimalarials,53,93,100–106 especially in paediatric formulations or when the drug has a narrow therapeutic window.12
In addition, there are many reports that anti-infective drugs of poor quality such as anti-TB agents and antimalarial drugs may cause treatment failure7,9,13,48 and can lead to substantial morbidity or mortality.71,93,100–103,107–109 Other studies report the number of deaths, which can be very high because of counterfeit drugs, such as the most well-known major incident concerning 2500 deaths in Niger in 1995 from a counterfeit meningitis vaccination.98
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Emergence of drug resistance |
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Other consequences of the problem of counterfeit and/or substandard antimicrobial drugs include the substantial effect on the growing global problem of antimicrobial resistance,7,9,13,48 especially for diseases that are treated with combination therapy such as tuberculosis,6,65,108 malaria due to Plasmodium falciparum39,45,109 and HIV. Most drug failures are due to lower contents or dissolution scores, which is comparable with taking low doses of the drug. As a result although some bacterial agents are still susceptible to common antibiotics in industrialized countries, in some other developing countries, the proportion of multiresistant strains in various bacterial species has greatly increased.36
Moreover, substandard narrow-spectrum antibiotics may create the wrong impression that the antibacterial agents themselves are ineffective and, thus, lead prescribers to unnecessarily opt for newer broad-spectrum antibiotics that have not yet been copied by unscrupulous manufacturers as their first-line treatment for many infections.99
According to WHO, the consequences of this are obvious: (i) relatively cheap drugs will become ineffective; (ii) the loss of such drugs will require new drug development, which will be more expensive and will further disadvantage patients in the developing countries; and (iii) selection of drug-resistant pathogens will lead to increased morbidity, mortality and a significant economic burden on developing regions of the world.110 Another risk of using counterfeit drugs is that with the increased mobility of persons, the transmission of drug-resistant strains of diseases from country to country and within regions will also increase.
Examples of substandard antimicrobials that lead to spreading of resistance include chloramphenicol and co-trimoxazole6 and antimalarials111 such as artemisinins,39,112 chloroquine113,114 and mefloquine.115
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Other consequences |
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The counterfeiting of pharmaceuticals has serious consequences for consumers, healthcare providers, drug manufacturers and governments.116 There can be significant decline in confidence in public health systems, healthcare professionals and in government agencies involved in distributing drugs.116 Health practitioners can also lose confidence in the medications that they rely upon because of false reports of drug resistance.45,117 On the other hand, the financial consequences of counterfeit medicines for the companies producing the genuine product can be enormous.118–120 Finally, the financial impact for consumers can also be significant, mostly due to higher prices for drugs, especially in countries like the USA.116
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Interventions |
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There is clearly no simple solution to the problem of counterfeit anti-infectives and several strategies are required. WHO has established guidelines against counterfeiting,121 which require cooperation between government organizations, health workers, industry and civil society.1,81,122–124 The Declaration of Rome, arising from the WHO International Conference on Combating Counterfeit Medicines, calls for the formation of an International Medical Products Anti-Counterfeiting Taskforce.125,126 Moreover, as a response to the increased threat of counterfeit drugs in the USA and throughout the world, the US FDA established the Counterfeit Drug Task Force. Task force strategies for combating drug counterfeiting include using advanced technology, security business practices and regulatory requirements, creating rapid alert and response systems, developing education and public awareness programmes and addressing international issues.68,127–130 FDA has also issued many measures to combat counterfeit antimicrobials in many publications.127,130–141 WHO has issued guidelines for combating counterfeit medications,1,6,15,22–25,46,50,57,77,95,98,122,126,142–150 but their effect in reducing counterfeiting of medications has not been assessed by studies.
However, although guidelines have been produced,95 most developing countries do not have the infrastructure and financial resources to implement them.1,12,75 For example, in Nigeria, efforts to control this problem were not very successful.151 In contrast, other research efforts were more effective. Interventions developed by WHO to reduce fake antimalarials in southeast Asia involved drug packaging such as blister packaging, public information campaigns and assessments of drug quality and improved drug compliance.152
Increased legal measures,153 including even death penalties (e.g. in China),154 and increased inspection and drug regulation from governments have also been implemented as means to combat counterfeit drugs. However, there is only one published study examining the efficacy of such interventions,42 in which the quality of antimicrobials was examined in districts in Laos before and 2 years after random allocation to either regular or enhanced drug inspection. Although drug quality improved substantially over the 2 years, no significant differences were found between the regular and enhanced drug inspection districts.42 Prosecution of counterfeit antibiotics has been successful in some of the cases, e.g. in China.155
On the other hand, increased public awareness of the problem of counterfeit drugs is of paramount importance and governments and companies have issued warnings about specific counterfeited products. For example, Nigeria and Thailand have developed informative web sites and such campaigns had some success, e.g. in Cambodia.45 WHO has issued guidelines that consumers should follow, such as to check for abnormal appearance of packaging, to avoid buying suspiciously inexpensive medicines and to buy only from licensed pharmacies; however, their effectiveness is unknown.1
Finally, interventions related to quality control and good manufacturing practice are necessary to reduce the prevalence of substandard drugs, but these are not complicated by criminal motives as is the case with counterfeit drugs.
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Limitations of the review |
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Our review has several limitations including the inclusion of only studies in the English language and the search of only the PubMed database and major newspaper articles and Internet web sites found through the Google search machine. In the current manuscript, we could identify few studies with sufficient methodology and as a result, conclusions regarding low quality of specific classes of antimicrobials could not be made in some cases. In many reports on the quality of drugs in developing countries, the terms counterfeit and substandard drugs have been used interchangeably and the authors often do not distinguish between counterfeit and substandard drugs. Many studies measure the percent of available drugs that do not meet minimum pharmaceutical standards or do not possess the proper quantity of active ingredients, but, in most of them, there was no criminal investigation on the source of the medications so it was not specified whether the substandard medications were also counterfeit.53,156
In addition, although in some studies the source of the low-quality antimicrobial agent is reported (Table 1), this source is not specified in the vast majority of the reports published and it is not possible to distinguish whether the reference is to a generic or to the original trade name product. This makes studying of the problem of substandard antimicrobials problematic with regard to application of GMP and the implementation of international standards in the manufacturing part of the industry.
Moreover, variability in definitions between different studies using different pharmacopoeial standards often makes direct comparisons difficult. Many of the previous reports on counterfeit drugs have been based on case reports on failure to attain the expected therapeutic effect, or reports investigating a small sample of products belonging to different classes of drugs.10,15,157 Counterfeit drugs exist on the market sporadically, and the absence of counterfeit drugs in some studies could be due to the sampling window or sample size. Other reports constituting the WHO database have remained confidential, unpublished or published for limited distribution.15 Finally, many of these studies had methodological limitations specifically with regard to sampling and data analysis and were not necessarily representative for the whole country that was studied.
Thus, despite the scale of the problem of low-quality medications, there is little research on poor quality drugs. There are very few studies on the prevalence of counterfeit and substandard drugs with sufficient methodology including random sampling.12 Future research efforts are needed to clearly study the problem of low-quality medications with adequate design to avoid bias. Publications describing drug quality should also provide manufacturer's names as stated on the packaging,108 but only a small portion of published studies provide this information.158 Such data are required to better define the problem by providing reliable prevalence estimates and by examining the effectiveness of interventions to confine this menace.
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Conclusions |
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In summary, the data of the reviewed studies suggest that the problem of counterfeit and/or substandard antimicrobial drugs has a large dimension with considerable direct and indirect effects on global public health. The use of low-quality drugs can result in adverse clinical outcomes such as lack of effect and treatment failure, risk of development of bacterial resistance, toxicity, side effects and even deaths. This problem can have important implications on the everyday practice of healthcare providers because not only physicians but also patients lose confidence in the effectiveness of antimicrobials. In the current manuscript, we have summarized the body of scientific evidence in an effort to define the problem more clearly. Several strategies are required to combat the problem of counterfeit anti-infectives including cooperation between government organizations, health workers, industry and civil society and WHO has announced specific guidelines. However, many of these measures cannot be implemented in many developing countries because of the lack of resources and therefore there is need for international coordination to fight the menace of counterfeit/substandard antimicrobials.
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Transparency declarations |
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None to declare.
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Supplementary data |
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Tables S1–S5 are available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/).
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Footnotes |
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The first two authors have equally contributed to the work. 
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Acknowledgements |
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This study received no funding.
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References |
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