PUBLIC HEALTH CONSEQUENCES

A reliable, good-quality medicine supply is essential for health, but it is often missing in countries with weak regulatory systems (Ratanawijitrasin and Wondemagegnehu, 2002). The fallout of falsified and substandard medicines includes poisoning, untreated disease, early death, and treatment failure.

Untreated Disease, Disease Progression, and Death

Medicine is intended to cure patients, or at least to relieve symptoms or slow the progression of a disease. There is also useful information in treatment failure. When prescribing medicines of known content and potency, the clinician may suspect inadequate dosing, drug resistance, or misdiagnosis if the patient does not respond to treatment as expected. These inferences are central to the practice of medicine. The Partnership for Safe Medicines, an American nonprofit, encourages doctors to suspect counterfeit¹ drugs in cases of treatment failure (PSM, n.d.), but there is little published evidence to suggest they do so. Advising physicians to consider the possibility of medicine fraud suggests that they have a way to verify it. In parts of the world where such assays are too costly or too technologically complicated to pursue, this information is usually unknowable. Confirmed accounts of drug failure are only a fraction of the larger, mostly invisible, problem.

Research at the medicine store can help illuminate these problems. A random sample of all known medicine shops in three districts of Ghana found the uterotonic drugs oxytocin and ergometrine to be of uniformly poor quality: 89 percent of the samples tested were below British Pharmacopoeia specifications though only 2 percent were expired (Stanton et al., 2012). Unicef, the United Nations Children's Fund, estimates the maternal mortality ratio in Ghana to be 350 per 100,000 live births (Unicef, 2003), of which hemorrhage, a condition treated with uterotonic drugs, is the most common cause (Asamoah et al., 2011). Even in Ghanaian hospital studies, where one would expect hemorrhage to be an uncommon cause of death, it accounts for an estimated 17 to 22 percent of maternal deaths (Ganyaglo and Hill, 2012; Lee et al., 2012). Increasing access to emergency obstetric care is a key piece of any strategy to reduce maternal mortality (Campbell and Graham, 2006), one that lies on the assumption that lifesaving uterotonic medicines are of reliable potency. Research suggests they are not, even in a middle-income country like Ghana.

The type of study Stanton and colleagues undertook in Ghana is rare. They were able to draw conclusions about uterotonic drug quality because their data represented a random sample of drugs from an almost exhaustive sampling frame of known pharmacies, chemical shops, and other dispensaries in their study area (Stanton et al., 2012). The identification of falsified and substandard medicines is more often incidental, found in newspaper accounts or uncovered in research that had a different primary aim.

Medications for Chronic Diseases

In 2009 a southwest China newspaper reported on a substandard version of the diabetes drug glibenclamide (also called glyburide) found to contain six times the pharmacopeial standard dose (Xiang, 2009). The medicine was tested only after killing two people and injuring nine (Cheng, 2009; Xiang, 2009). Like oxytocin and ergometrine, glibenclamide is a WHO essential medicine, as is only one other oral diabetes drug, metformin (WHO, 2011c). Metformin too has been the subject of quality concerns. In a convenience sample of pharmacies in Lagos, Nigeria, researchers found that four of eight popular brands of metformin tablets failed one or more pharmacopeial tests of bioequivalence (Olusola et al., 2012). These are troubling findings, given that an estimated 80 percent of the world's 347 million diabetics live in low- and middle-income countries, where medicines quality is most variable, and diabetes case-fatality exorbitantly high (Unachukwu et al., 2008; WHO, 2011a). Dora Akunyili, the former director of the Nigerian drug regulatory authority, worked against pharmaceutical fraud, a cause she committed to after her diabetic sister's death from fake insulin (Cheng, 2009; Lemonick, 2005).

Medication for other chronic diseases has been compromised in developing countries. A Rwandan study on drug stability found that 20 percent of medicines in a sample of Kigali and Butare pharmacies were substandard at the time of purchase (Twagirumukiza et al., 2009). Two studies of the antihypertensive amlodipine's quality in south Nigeria found problems: one study reported 30 percent of samples failed pharmacopeial tests for content uniformity (Eichie et al., 2011) and, in another, all samples failed (Olajide et al., 2010). The management of diseases such as type 2 diabetes and hypertension depend on maintenance medication and monitoring. The sheer amount of products used to treat these conditions raises the patients' lifetime risk of encountering a bad product, even in countries with stringent regulatory authorities (see Box 2-1). The need for reliable medicines in low- and middle-income countries will become more pronounced as the burden of chronic disease increases in these countries. Already cardiovascular disease is the main killer of adults in low- and middle-income countries, the proper medical treatment of which is often neglected (Gaziano, 2007; Yusuf et al., 2011).

BOX 2-1

Defective Glucose Test Strips. In October 2006, the FDA recalled two batches of blood glucose test strips used in LifeScan, Inc. OneTouch Ultra brand blood glucose monitors after LifeScan notified the agency that it had received a number of customer complaints. (more...)

Maintenance medication for cardiovascular disease is a vulnerable target for fraud, but the need for these drugs is still unmet in much of the world (Gaziano, 2007). In developing countries, there has been a greater emphasis on controlling infectious disease, especially the infectious diseases of childhood. Considerable research indicates that the anti-infective drugs used to do this are often compromised in poor countries.

Medications for Infectious Diseases

Since 1999 the WHO has known that antibiotics are commonly falsified or made improperly (Wondemagegnehu, 1999). In the 1990s antibiotics accounted for over 45 percent of the 771 cases of falsified and substandard medicines brought to the WHO's attention (Wondemagegnehu, 1999). A more recent survey in Egypt, Jordan, Lebanon, and Saudi Arabia found more than half of antibiotics sampled to be substandard (Kyriacos et al., 2008). A similar survey in Burma uncovered substandard drugs in 16 percent of amoxicillin and 13 percent of ampicillin samples (Wondemagegnehu, 1999). More recently, a survey of amoxicillin in the capital of Papua New Guinea found all samples outside of pharmacopeial specifications; 14 percent had undetectable levels of active ingredient (Nair et al., 2011). Chapter 3 describes the depth of the problem of fake antibiotics in more detail.

In most low- and middle-income countries β-lactam antibiotics, an inexpensive and widely available class of drugs that includes penicillin and amoxicillin, are the first-line treatment for dozens of bacterial infections, including scarlet fever, pneumonia, and respiratory and urinary tract infections (Byarugaba, 2004). Pneumonia, for example, is the leading cause of death in children under 5 and accounts for 18 percent of all child deaths in the world (Unicef and WHO, 2006; WHO, 2011b). The pathogen Streptococcus pneumoniae causes most of the world's pneumonia. Alone it accounts for as much as 12 percent of all child deaths worldwide (O'Brien et al., 2009). Unicef's recommended strategy for preventing pneumonia deaths is recognizing sickness in the child, seeking medical care, and treating with antibiotics (Unicef and WHO, 2006). This will remain the best strategy until the pneumococcal conjugate vaccine becomes more widely available. The treatment of pneumonia and other devastating bacterial infections depends on effective antibiotic supply. No research to date has attempted to quantify the proportion of child deaths attributable to falsified and substandard medicines, but Table 2-1 presents the most common causes of child death and links them to verified reports of substandard medicines.

TABLE 2-1

Medicines Used to Treat the Most Common Causes of Child Death Are Compromised in Developing Countries.

Vaccines are also important in the control of infectious disease. Chapter 5 describes the medicines supply chain in developing countries; in general, the vaccine supply chain is simpler, if only because Unicef manages the parts of the chain between the manufacturer and the national port of entry (Kauffmann et al., 2011). Cases of falsified and substandard vaccines are rare, but Box 2-2 describes some.

BOX 2-2

Deaths from Substandard and Falsified Vaccines. Vaccines are complicated to make, and there are relatively few manufacturers supplying the world market. Vaccines are generally procured in bulk by governments or UN agencies in a supply chain with few intermediaries. (more...)

If antibiotics are some of the oldest and most widely used medicines in the world, antiretrovirals are their opposites: new medicines, prescribed in complicated regimes, to a relatively small segment of the population. An exhaustive WHO survey of antiretroviral drug quality in seven sub-Saharan African countries and a variety of treatment centers found reliable good quality in HIV medications (WHO, 2007). Only 1.8 percent of the drugs tested failed to meet quality specifications, and even those were “[not] serious failures, i.e., no critical deficiencies which would pose a serious risk to patients” (WHO, 2007, p. 19).

Some more recent reports suggest that falsified antiretroviral drugs may circulate in African countries. In September 2011, falsified and substandard versions of the triple combination therapy Zidolam-N surfaced in Kenya, many samples molding and crumbling in the packages (Taylor, 2011). A year later, in Tanzania, the regulatory authority uncovered falsified antiretrovirals at a district hospital (Athumani, 2012). These failures put HIV patients at risk for disease progression and favor the selection of resistant virus strains (WHO, 2003). As their viral loads increase, these patients are also more likely to transmit the infection, impeding efforts to control the virus.

Although data suggesting compromised antiretroviral drug quality are mixed, there is substantial evidence, presented in Chapter 3, that antimalarials are often of poor quality. Substandard and falsified malaria drugs are especially common in malaria-endemic parts of Africa and Asia. In 2003, substandard sulfadoxine-pyrimethamine was used to treat a malaria epidemic in northwest Pakistan refugee camps (Leslie et al., 2009). Researchers concluded that, as the strain of P. falciparum they identified was 90 percent curable when using standard sulfadoxine-pyrimethamine drugs, the substandard medicines, procured from local manufacturers because of drug shortages, were a causal factor in what initially presented as drug-resistant malaria (Leslie et al., 2009). In this example, the effects of the substandard medicine were promptly mitigated. Health workers diagnosed the parasite with microscopy, monitored drug resistance, and checked drug quality using procedures described in the U.S. Pharmacopeia monograph. Good care during initial infection and treatment with an effective second-line drug prevented any deaths, and the onset of cooler weather stopped transmission (Leslie et al., 2009). The prognosis for most people treated with poor-quality antimalarial drugs is worse. Not only will their malaria be untreated, but inadequate treatment favors the selection of resistant parasites, which threaten their entire communities.

Treatment Failure

Individual patients have much to lose from substandard and falsified medicines. These products also encourage drug resistance and thereby threaten population health today and for future generations. This is a particular concern with substandard products where the dose of active ingredient is low and variable and with falsified products diluted by criminals in an effort to pass screening assays. Drug resistance is common in pathogens with short life cycles: viruses, bacteria, and protozoa. Poor-quality antimicrobial medications, taken frequently and, in poor countries, generally taken without professional supervision, contribute to drug resistance.

Antimicrobial Resistance

Antibiotics should be used only when indicated, in the appropriate dose, and for the correct length of time. Ensuring the proper treatment with the right combination of drugs is the underlying principle of Directly Observed Treatment—Short Course (DOTS), the internationally accepted method of tuberculosis surveillance and treatment (WHO SEARO, 2006). DOTS also depends on a safe and reliable drug supply. Poor-quality drugs have been cited as a causal factor for the rise of multidrug-resistant tuberculosis (Kelland, 2012). Over time, the bacteria causing tuberculosis have become increasingly drug resistant. Multidrug-resistant tuberculosis precedes extensively drug-resistant tuberculosis, and finally, sometimes, totally drug-resistant tuberculosis (Udwadia, 2012). Extensively drug-resistant strains of tuberculosis account for about 6 percent of incident infections worldwide, but much more in China, India, and the former Soviet Union (Jain and Mondal, 2008). Figure 2-1 shows the increasing incidence of multidrug-resistant tuberculosis around the world.

FIGURE 2-1

Increasing incidence of multidrug-resistant tuberculosis (MDR-TB). SOURCE: WHO, 2011b.

Drug-resistant bacteria often surface in hospitals, causing infections that are difficult to treat and are an important killer of adults in low-and middle-income countries (Okeke et al., 2005b; WHO, 2012a). It is difficult to estimate the burden of antimicrobial resistance in low- and middle-income countries, in part because of the dearth of data, especially from francophone Africa, the Asian Pacific, and the former Soviet Union (Okeke et al., 2005a). The data that do exist are grim. Multidrug-resistant staphylococcus, an emerging problem in India and sub-Saharan Africa (Parasa et al., 2010; Vincent et al., 2009), accounts for more than half of all nosocomial infections in parts of Latin America (Guzmán-Blanco et al., 2009). (See Figure 2-2.)

FIGURE 2-2

Percentage of nosocomial Staphylococcus aureus isolates with resistance to meticillin in studies in Latin American countries. NOTE: Countries in orange are those with >50 percent of nosocomial S. aureus isolates were found to be meticillin-resistant (more...)

In a qualitative study in Orissa, India, doctors, veterinarians, and pharmacists cited poor-quality antibiotics as a cause of drug resistance, but mentioned it only in passing, focusing more on patient and provider behaviors (Sahoo et al., 2010). This is consistent with most public health literature, which gives great deal of attention to the overuse of antibiotics as contributing to the rise of antimicrobial resistance in general (Byarugaba, 2010; Okeke et al., 2005b) and drug-resistant pneumonia in particular (Unicef and WHO, 2006). Comparatively little work, however, discusses the role of drug quality in encouraging bacterial resistance. Antibiotics that contain low doses of active ingredient cause low circulating levels of the drug in the patient. This contributes to treatment failure and selectively favors the growth of drug-resistant organisms (Okeke et al., 2005b). Resistance is most common among the oldest and least expensive families of antibiotics (Okeke et al., 2005b).

According to a recent Tufts University estimate, it costs more than $1.3 billion to bring a new drug to market (Kaitin, 2010). Antibiotics in particular offer pharmaceutical companies a low return on investment; patients take them for only a week or two, in contrast to lifetime regimes of maintenance drugs. There would be even less monetary incentive to develop antibiotic for only the poorest parts of the world. Preserving antibiotics is imperative and depends on maintaining drug quality as much as on encouraging rational use.

Antimalarial Resistance

Through a conceptually similar mechanism, selectively allowing the growth of drug-resistant parasites by exposing them to subtherapeutic doses of medicines, falsified and substandard drugs favor survival and spread of resistance to antimalarial medicines. Drug-resistant parasites of particular concern are the malaria parasites Plasmodium falciparum and Plasmodium vivax.

Artemisinin combination treatments are effective in treating falciparum malaria (WHO, 2011d). They have been the recommended first-line treatment for falciparum malaria everywhere in the world since 2001 (WWARN, 2012d). In areas where these drugs are available and appropriately used, malaria deaths have dropped dramatically (WHO, 2011d).

Drug resistance could undo the success that artemisinin therapies have won, however (see Box 2-3). A recent review estimates that about 35 percent of the antimalarial medicines in Southeast Asia are substandard, and 36 percent can be classified as falsified (Nayyar et al., 2012). The same researchers found similar patterns in sub-Saharan Africa, where about 35 percent of antimalarials are substandard and 20 percent are falsified (Nayyar et al., 2012). In both regions, underdosing the active ingredients is far more common than overdosing (Nayyar et al., 2012). Already, 8 of the 12 major antimalarial drugs used in the world have been falsified, including products labeled as of mefloquine, but containing sulphadoxine-pyrimethamine and no mefloquine, and a product labeled as artesunate, but containing 6 percent chloroquine and no artesunate (Newton et al., 2006). Poor-quality medicines supply a subtherapeutic dose that selectively encourages the emergence of partially resistant pathogens (Talisuna et al., 2012).

BOX 2-3

The WorldWide Antimalarial Resistance Network. Despite the success of malarial control programs starting in 2004, malaria is still a major cause of death, especially in Africa (Murray et al., 2012). WHO estimates that about 655,000 people die from malaria (more...)

Underdosing with antimalarials causes low concentrations of active drugs in patients and selective pressure to breed resistant parasites (Dondorp et al., 2011; Sengaloundeth et al., 2009; White et al., 2009). In Thailand investigators have observed a progressive lengthening of the time it takes for patients to clear malaria parasites from their bloodstream during treatment, suggesting that the parasites are becoming more resistant to artemisinin (Phyo et al., 2012). Resistance is heritable from one generation of parasite to the next; the relatively resistant parasites persist and are transmitted (Anderson et al., 2010). So far, artemisinin resistance has been documented only in Southeast Asia, but its persistence and spread could threaten global malaria control programs. No other antimalarial drugs are available as alternatives. If the current first-line therapy is lost because of resistance, malaria deaths will again increase.

Other Antiparasitic Resistance

Confirming drug resistance in parasites is more complicated than the same assessment in bacteria (Cabaret, 2010). There is good evidence, however, that underdosing with anthelmintic medication has favored survival of resistant worms, and substandard medicines are a noted contributor to anthelmintic resistance in both humans and animals (Geerts and Gryseels, 2001).

Drug resistance threatens efforts to contain other neglected tropical diseases. Visceral leishmaniasis, also called kala azar, is a parasitic disease that affects a half a million people per year, mostly in South Asia, and also in Brazil and Sudan (Sundar, 2001). Untreated kala azar is fatal, but pentavalent antimonial drugs have been a reliable therapy since the 1930s. Pentavalent antimonials are still a first-line treatment today, but drug resistance has diminished the potency of these drugs (Sundar, 2001). A high-osmolarity batch of pentavalent antimonials induced congestive heart failure, killing three kala azar patients and sickening many more at Benares Hindu University hospital in the late 1990s (Sundar et al., 1998). Since then, substandard medicines have been a suspected factor in the increasing resistance of the kala azar parasites to traditional treatment (Sundar, 2001). Newer therapies, such as miltefosine, hold promise for containing the disease, but this promise will not be realized unless the drugs are of reliable quality. As recently as 2012, a convenience sample of miltefosine in Bangladesh found the drugs to be uniformly devoid of any active ingredient (Dorlo et al., 2012).

ECONOMIC AND SOCIAL CONSEQUENCES

Substandard and falsified medicines effect health directly and pose a danger to individual patients and to public health. They also have economic and social consequences, including the direct costs of additional treatment and indirect social costs of lost confidence in the health system and the government.

Costs to the Health System

First, the use of falsified and substandard medicines costs the health care system. Providers do not usually suspect that the drugs they prescribe are of poor quality and will respond to a poor therapeutic response by ordering more tests or by repeating the course of treatment. In poor countries, where medicines rank second only to food as a household expense (Cameron et al., 2008), an increase in the family medicines bill can be a palpable hardship. When government or donors supply medicines, they shoulder the added costs of falsified and substandard drugs.

Chapter 4 describes the pressure on procurement agencies to fill drug orders for the lowest prices, a false frugality that can cause the wasting of an entire medicines budget on drugs with insufficient active ingredients. The costs only grow when expensive drugs are targeted or when they are sold in rich countries. It is not yet clear how much patients and insurance companies paid for falsified Avastin during the 2012 crisis, but the Wall Street Journal found that the fake product sold for almost $2,000 per vial (Weaver and Whalen, 2012).

Pharmacy in Cambodia

SOURCE: Hen Sophal in Pharmacide Arts, an exhibit of Southeast Asian artists.

Drug resistance will increase costs to the health system, and not only because of increased clinical attention. Drug resistance reduces the effective life of a drug. Already the cheapest, oldest classes of anti-infective drugs are becoming useless. Society must bear the expense of new drug development, an ever-increasing cost (see Figure 2-3), because resistant pathogens require treatment with more complex drugs. A 2010 estimate put the cost of developing a single drug at $1.3 billion (Kaitin, 2010), and a 2003 study showed that the cost of drug development grew 7.4 percent faster than inflation (DiMasi et al., 2003).

FIGURE 2-3

The increasing costs of drug development. SOURCE: PhRMA, 2012.

Aside from the direct financial costs of treatment, there are opportunity costs incurred to patients who miss work for additional doctors' visits or become too sick to work. Chapter 3 will explain that the burden of falsified and substandard medicines is borne mostly by the poor in South and Southeast Asia and sub-Saharan Africa. Transport costs and opportunity costs are a known obstacle to health care for these patients (Whitty et al., 2008). Customers at gray pharmaceutical markets, including flea markets, unlicensed medicine shops, and bazaars, are often there because they cannot afford to miss work for a formal consultation (Whitty et al., 2008). For example, participants at the São Paulo site visit for this study explained that although medicines are free through the public health system in Brazil, miners and other daily-wage workers circumvent this system. They continue working and self-treat with medicines of dubious quality from the gray market. In Brazil, as in many parts of the world, falsified and substandard medicines extract the highest costs from those who can afford the least.

Scientists and policy makers in developing countries are aware of the toll falsified and substandard drugs take on their health systems. A 2009 WHO expert working group rated fake medicines as a top priority for research in developing countries (Bates et al., 2009).

Patients may begin to distrust modern pharmacies after experiences with falsified and substandard drugs. In Ugandan villages, the proportion of positive responses to the question “Do you expect that the antimalarial medicines sold by the nearest drug shop are fake?” correlates roughly with the actual percentage of poor-quality drugs (Björkman-Nyqvist et al., 2012).

As well as having accurate doubts about individual pharmacies, consumers in places where fake drugs circulate have reason to lose faith in the public health system. A recent systematic review suggests that patients across a range of developing countries already have poor perceptions of the health system, especially the technical competence and clinical skills of the staff and the availability of medicines (Berendes et al., 2011). Poor-quality medicines stand to damage the perception of the health system even more. Qualitative research in China suggests that patients view the loosely regulated private health care system poorly, seeing it as rife with “fake doctors” and “fake drugs” (Lim et al., 2004, p. 227).

During a site visit to Brazil, the IOM delegation heard that, although the Brazilian drugs regulatory authority is strong, the public still doubts the quality of many medicines. Participants consistently attributed this poor confidence to unplanned pregnancies following a 1998 lapse in the quality of oral contraceptives (Associated Press, 1998; Goering, 1998). Anvisa, the Brazilian drugs regulatory authority, was created in response to this and other medicine quality problems (Csillag, 1998). Rumors about contraceptive quality linger in Brazil, a kind of urban folklore. They are evidence, however, that fake medicine can do long-term damage to the reputation of the health system.

Social and Developmental Costs

In a larger sense, trade in falsified and substandard medicines undermines not just the health system but all public institutions. Corruption in the health system can cause patients to assume the drug supply is substandard (BBC, 2012). Falsified medicines are often the business of criminal cartels, including the Camorra crime group in Naples, the Russian mafia, and Latin American drug cartels, and terrorist organizations, such as Al-Qaeda and Hezbollah (Findlay, 2011). These organizations run profitable and untaxed businesses. Organized crime flourishes under authoritarian governments and weak rule of law, both common in developing countries (UNODC, 2009). Criminals grow wealthy under either system, eventually wealthy enough that tacit (or active) collaboration becomes necessary for private citizens and politicians to survive (UNODC, 2009). When criminals control politicians, governments cannot be trusted. Donors are then obliged to withhold development aid, as several countries have done in response to corruption in the Zambian health ministry (BBC, 2010; WHO, 2009).

The sale in falsified medicines funds other criminal activities, buys weapons and ammunition, and conveys power and influence to corrupt officials (Findlay, 2011; UNODC, 2009). The United Nations Office on Development and Crime (UNODC) reckons that in West Africa the sale in falsified medicines may be worth as much as the billion-dollar oil and cocaine trafficking industries; their estimate of the worth of trafficked antimalarials alone is more than $400 million (see Figure 2-4).

FIGURE 2-4

Comparative values of trafficking flows in West Africa. SOURCE: UNODC, 2009.

Chapter 4 describes why medicines fraud is sometimes called the perfect crime. Fake medicines generate income for criminals, and only the weakest evidence, if any, ties them to their crime. Acute cases of medicine poisoning can elicit public outcry, but more often bad drugs go unnoticed, blending in with lawful business. Victims of falsified and substandard drugs usually do not even know they are victims and are therefore deprived of their right to redress. The UNODC described the traffic in fake drugs as both as cause and an effect of political instability, explaining, “Living in a society where such widespread and serious fraud can occur undermines confidence in government, but the effects are so diffuse and uncertain that they are unlikely to generate an organized political response” (UNODC, 2009, p. 6). In many parts of the world, falsified and substandard medicines further erode the already weak political infrastructure that allows them to circulate, part of a vicious cycle of poverty and crime.

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Footnotes

1

The Partnership for Safe Medicines uses the term counterfeit broadly, the way this report uses falsified. See page 23.