3

The Magnitude of the Problem

It is difficult to accurately measure the burden of falsified and substandard drugs. As Chapter 2 mentions, some of the understanding of the problem comes from alerts in gray literature, including investigative journalism and industry and association reporting. Although these sources provide some insight, they do not provide an accurate estimate of the true magnitude of the problem. National regulatory authorities and drug companies keep records on fraudulent medicines; a broader understanding of the problem comes from peer-reviewed literature. There are few epidemiologically rigorous, peer-reviewed studies on the prevalence of falsified and substandard drugs.

This chapter presents the results of a cross section of government and industry data and peer-reviewed and gray literature about the global burden of falsified and substandard drugs. It does not summarize every study, but rather gives an overview of important trends.

INDUSTRY AND GOVERNMENT DATA

Both industry and governments have data on medicines quality, but little of this information is public. There was a time when this was a conscious secrecy, an effort to avoid discrediting the public health system and drug companies, expressed in the Royal Pharmaceutical Society’s 1989 statement “no great publicity [about fake drugs] should be sought because it could damage public confidence in medicines” (Cockburn et al., 2005; More UK debate on counterfeits, 1989). The society has since changed its policy, but the essence of the problem remains. Governments may wish to control rumors that can be seen as damaging to their institutions. Similarly, drug companies, both innovator and generic, may withhold information about falsified and substandard medicines on the grounds that such stories discourage patient confidence in their products (Cockburn et al., 2005).



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3 The Magnitude of the Problem It is difficult to accurately measure the burden of falsified and sub- standard drugs. As Chapter 2 mentions, some of the understanding of the problem comes from alerts in gray literature, including investigative journalism and industry and association reporting. Although these sources provide some insight, they do not provide an accurate estimate of the true magnitude of the problem. National regulatory authorities and drug com- panies keep records on fraudulent medicines; a broader understanding of the problem comes from peer-reviewed literature. There are few epidemio- logically rigorous, peer-reviewed studies on the prevalence of falsified and substandard drugs. This chapter presents the results of a cross section of government and industry data and peer-reviewed and gray literature about the global burden of falsified and substandard drugs. It does not summarize every study, but rather gives an overview of important trends. INDUSTRY AND GOVERNMENT DATA Both industry and governments have data on medicines quality, but little of this information is public. There was a time when this was a con- scious secrecy, an effort to avoid discrediting the public health system and drug companies, expressed in the Royal Pharmaceutical Society’s 1989 statement “no great publicity [about fake drugs] should be sought because it could damage public confidence in medicines” (Cockburn et al., 2005; More UK debate on counterfeits, 1989). The society has since changed its policy, but the essence of the problem remains. Governments may wish to 85

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86 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Key Findings and Conclusions • Public data on the magnitude of the problem of substandard and falsified medicines are limited. • The illegal trade and manufacture of medicines are a global problem, disproportionately affecting low- and middle-income countries. • Countries with weak regulatory oversight and law enforcement attract illegitimate manufacturers, while countries with strict law enforcement repel them. • Government and intergovernmental agencies, such as the U.S. Food and Drug Administration and Interpol, have taken action against sub- standard and falsified medicines. control rumors that can be seen as damaging to their institutions. Similarly, drug companies, both innovator and generic, may withhold information about falsified and substandard medicines on the grounds that such stories discourage patient confidence in their products (Cockburn et al., 2005). There is a difference between secrecy and appropriate discretion with evidence for pending criminal prosecutions. The committee recognizes that undercover intelligence informs law enforcement agencies’ actions against criminals. Prematurely releasing confidential information about pharma- ceutical crime can compromise an investigation. Too often, however, gov- ernments and industry withhold information years after incidents pass (Cockburn et al., 2005). Regulators should be able to access this data so that they can communicate it to the public as appropriate, as it informs consumer safety and can trigger epidemiological research on drug quality. There is also value in sharing information on falsified and substan- dard medicines internationally. The modern pharmaceutical supply chain is complex. Drug manufacturers source chemicals from around the world, and different factories process ingredients into a final formulation that is packaged, repacked, and sold in many different countries. The chances that a drug quality problem in one country affects that country alone decrease when products travel along global supply chains. The interconnectedness of the drug supply chain makes it imperative that countries share information on falsified and substandard drugs. The Pharmaceutical Security Institute Incident Reporting System The Pharmaceutical Security Institute (PSI) is a nonprofit organization composed of the security departments of 25 major pharmaceutical compa-

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THE MAGNITUDE OF THE PROBLEM 87 nies (PSI-Inc., 2012b). These companies share information on illegal phar- maceutical manufacture and trade. Because criminals who make and traffic illegal drugs target a wide range of companies’ products, cooperation and data sharing among companies adds depth to their collective understanding of the problem. The institute maintains a secure database to which members report cases of fraudulent manufacture and mislabeling of drugs, as well as cases of fraudulent packaging. The database is organized into incidents, “discrete event[s] triggered by the discovery of counterfeit, illegally diverted, or stolen pharmaceuticals” (PSI-Inc., 2012a). A unique tracking number links every incident to a distinct date, time, place, and product. Incidents can vary in size; sometimes, small amounts of a single product are affected, other times large quantities of many products (PSI-Inc., 2012a). Some incidents last for years while others are resolved in 1 year. Incidents that lasted several years are dated with the year in which the incident started (PSI-Inc., 2012a). An analysis of the institute’s data gives an understanding of where law enforcement and regulators are active against the illegal trade and manu- facture of drugs. Some countries with serious problems never appear in incident reports because there is little political will for action. For the same reason, some countries with transparent and accountable governments consistently appear in the ranking of numbers of seizures by countries (PSI data shared with the committee, Thomas Kubic, PSI-Inc., July 11, 2012). Table 3-1 presents the 2011 rankings of the top 12 countries where PSI members detected1 or where police, customs, or drug regulators seized falsified products. The illegal manufacture and trade of medicines is transnational. Table 3-1 shows only those countries where government or industry staff found a bad product; many more countries stand to be affected by those products. If a shipment of falsified pills comes from China to the United States via India, then the incident report names all three countries. Table 3-2 ranks the 10 countries most often cited in PSI incident reports. The countries listed in Table 3-2 account for 56 percent of illegal manufacture, trade, or sale and 47 percent of diversion cases in the PSI 2011 database (personal communication, Thomas Kubic, PSI-Inc., December 26, 2012). In addition to naming affected countries, every incident report in the PSI database mentions the drugs targeted. Every therapeutic class of drugs is represented in these reports, though genitourinary, anti-infective, and cardiovascular drugs are the most often implicated (PSI data shared with the committee, Thomas Kubic, PSI-Inc., July 11, 2012). Criminal interest in cardiovascular disease drugs is a new trend; only in 2011 did that class 1 Detection means confirming though chemical or package analysis that the product is not what it purports to be.

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88 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS TABLE 3–1 Ranking of Seizures or Detections by Country, 2011 Country Incidents 1 China 279 2 United States 141 3 Japan 79 4 Germany 62 5 Pakistan 61 5 Peru 61 7 Colombia 59 8 United Kingdom 56 9 South Korea 47 10 Brazil 45 10 Russia 45 12 Taiwan 44 SOURCE: PSI data shared with the committee, Thomas Kubic, PSI-Inc., July 11, 2012. of medicines move into the top three most commonly targeted (PSI data shared with the committee, Thomas Kubic, PSI-Inc., July 11, 2012). This is consistent with other industry reports that drugs sold and restocked fre- quently are most often targeted (Mukherjee, 2012). PSI member companies identified 1,623 counterfeiting incidents in 2011. In about half of these incidents (n = 810) companies were able to do product and packaging analysis. Investigators found that most samples were fraudulent in both product and packaging (see Figure 3-1). A false product in legitimate packaging was the second most common result; Chap- ter 5 discusses this problem in more detail. Analysis of PSI data supports two main conclusions. First, falsified and substandard drugs are a global problem that affected at least 124 countries in 2011 (PSI data shared with the committee, Thomas Kubic, PSI-Inc., July 11, 2012). Twelve more countries were affected in 2011 than in 2010; African countries accounted for most of this increase (PSI data shared with the committee, Thomas Kubic, PSI-Inc., July 11, 2012). The data do not suggest anything about the relative burden of the problem in different countries, however. Indeed, countries with lax enforcement attract illegal manufacturers, and countries with vigorous law enforcement repel them.

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THE MAGNITUDE OF THE PROBLEM 89 TABLE 3–2 Ten Countries Most Named in PSI Incident Reports, 2011 Total Country Counterfeit a Diversion Theft b Incidents 1 China 504 8 0 512 2 United States 145 62 8 215 3 India 95 23 0 118 4 Brazil 47 47 3 97 5 Colombia 62 32 0 94 6 Japan 81 0 0 81 7 United Kingdom 61 17 2 80 8 Germany 64 10 0 74 9 Uzbekistan 35 37 0 72 10 Pakistan 64 7 0 71 NOTE: PSI = Pharmaceutical Security Institute; WHO = World Health Organization. aPSI uses the term counterfeit broadly, in accordance with the WHO definition: “one which is deliberately and fraudulently mislabeled with respect to identity and/or source. Counterfeiting can apply to both branded and generic products and counterfeit products may include products with the correct ingredients, wrong ingredients, without active ingredients, with insufficient quantity of active ingredient or with fake packaging” (WHO, 1992, 2009). See page 23. bIncident reports include thefts worth roughly $100,000 or more. SOURCE: PSI data shared with the committee, Thomas Kubic, PSI-Inc., July 11, 2012. Second, PSI data suggest that the problem is borne disproportionately by low- and middle-income countries. Figure 3-2 shows Business Monitor International’s (BMI’s) global distribution of pharmaceutical sales; Figure 3-3 shows geographic distribution of PSI’s 2011 incidents. Admittedly, the Asia category in both figures includes rich countries such as Australia and Japan (personal communication, Mariam Kahn, Business Monitor Inter- national, October 23, 2012). The higher cost of living, higher incomes, and greater access to medicines in North America and Europe also account for these regions’ large share of pharmaceutical sales. Nevertheless, North America and Europe make up almost two-thirds of the world’s combined pharmaceutical sales but account for only a quarter of global trade in illegal medicines. PSI data come from the investigations of multinational, innova- tor pharmaceutical companies. One would expect a bias in these data to developed country markets, where PSI member companies earn most of their profits. However, even PSI data suggest a serious problem with falsi- fied medicines in low- and middle-income countries.

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90 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS 34 12 70 Fake product, fake packaging Fake product, legitimate packaging Legitimate product, 145 549 fake packaging Undeclared active ingredient Fake active ingredient, otherwise legitimate product and package FIGURE 3–1 Results of packaging and product analysis, 2011. SOURCE: PSI data shared with the committee, Thomas Kubic, PSI-Inc., July 11, 2012. Government and Intergovernmental Investigations National regulatory agencies have the main responsibility for monitor- ing drug safety (WHO, 2012a). This includes routine postmarket surveil- lance and enforcement of regulations. Much of their information about falsified and substandard drugs is confidential, but their publications give a sense of the types of violations regulators find. The FDA Office of Criminal Investigations The FDA Office of Criminal Investigations takes action against criminal violations of the Food, Drug, and Cosmetic Act, such as illegal drug manu- facture, manufacture and sale of unapproved drugs, illegal importation, drug adulteration, and promotion of off-label uses for approved products (FDA, 2009a,b). In May 2012, the office briefed the committee on their work from 2003 to 2008. This presentation and a 2011 review of the agency’s drug criminal cases give some understanding of common problems with the drug supply in the United States (Devine and Jung, 2012; FDA, 2011). These data illustrate certain problems with the drug supply chain but are not a “scientific representation of current . . . trends or a comprehensive review of problems” (FDA, 2011, p. 4). The FDA has investigated increasingly more drug quality cases since

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THE MAGNITUDE OF THE PROBLEM 91 Latin America $70 Middle East $16 Africa $19 Asia $265 North America $358 Europe $329 FIGURE 3–2 Geographic distribution of pharmaceutical sales in $U.S. billions, 2011 data. SOURCE: BMI, 2012. Latin America 16% Middle East 5% Africa 3% Asia 51% North America 10% Europe 15% FIGURE 3–3 Geographic distribution of Pharmaceutical Security Institute incident reports, affected countries, 2011 data. SOURCE: Personal communication, Thomas Kubic, PSI-Inc., October 18, 2012.

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92 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS 19972 (Devine and Jung, 2012). Solid oral dosage forms (pills and tablets) are the most commonly investigated product types (FDA, 2011). Zyprexa, Viagra, Lipitor, Zoloft, and Risperdal are the top 5 brand-name products implicated in the 10 highest-volume cases (FDA, 2011). Problems with individual criminals are more common than problems with negligent busi- nesses; the FDA’s 2003-2008 review found that 86 percent of criminal in- vestigations were of individual suspects, and 14 percent were of companies (FDA, 2011). International Police Investigations Interpol is an international organization that facilitates police coopera- tion around the world (Interpol, 2012c). The organization gives training and investigative support to police in 190 member countries (Interpol, 2012c). Pharmaceutical crime, which the organization defines as “counter- feiting and falsification of medical products, their packaging and associated documentation, as well as the theft, fraud, illicit diversion, smuggling, traf- ficking, [and] the illegal trade of medical products and the money launder- ing associated with it” has been an Interpol work area since 2005 (Interpol, 2012d; Plançon, 2012). Interpol organizes their work into four operations: Operation Pangea (against illegal online pharmacies), Operation Mamba (in East Africa), Operation Storm (in Southeast Asia), and Operation Cobra (in West Africa) (Interpol, 2012a). Tables 3-3 and 3-4 give an overview of these operations. As Table 3-3 and 3-4 indicate, police have seized millions of pounds of suspect drugs in Interpol operations. Some police forces sample and re- port the quality of the products found in these seizures. The police are not obliged to undertake such investigations or report their results to Interpol; in many countries, testing even a small sample of confiscated product would overwhelm the national drug quality laboratory. Interpol does not publish information on the testing and sampling of seized products. Interpol has raised international awareness about falsified and substan- dard drugs through their media campaigns and work with police (Interpol, 2011a; Mullard, 2010). Nevertheless, the information presented in Tables 3-3 and 3-4 does not indicate which kinds of drugs are targeted or if the problem is changing over time. 2 The FDA refers to these as counterfeit drug cases. The agency uses a definition of coun- terfeit that includes both falsified and substandard as this report defines them. See Table 1-2.

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THE MAGNITUDE OF THE PROBLEM 93 TABLE 3–3 Operation Pangea Against Online Pharmacies, 2008-2012 Number of Operation Countries Name Participating Duration Year Results Pangea V 100 1 week 2012 • 3.75 million pills confiscated • Estimated value: $10.5 million • 18,000 websites shut down • 133,000 packages inspected and 6,700 confiscated • 80 suspects under investigation or arrest Pangea IV 81 1 week 2011 • 2.4 million pills confiscated • Estimated value: $6.3 million • 13,500 websites shut down • 45,500 packages inspected and 8,000 confiscated • 55 suspects under investigation or arrest Pangea III 44 1 week 2010 • 2 million pills confiscated • Estimated value: $6.77 million • 297 websites shut down • 87 suspects under investigation or arrest Pangea II 25 5 days 2009 • Identification of 1,200 websites engaged in pharmaceutical crime • 153 websites shut down • 59 suspects investigated Pangea I 10 1 day 2008 • Commercial websites taken down • Postal deposits monitored and parcels examined, packages containing suspected counterfeit medicines intercepted • Thousands of medicines withdrawn from circulation SOURCE: Adapted from Interpol, 2012b.

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94 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS TABLE 3–4 Operations Storm, Mamba, and Cobra, 2008-2011 Number of Operation Countries Name Participating Duration Year Results Storm II 8 1 month 2010 • 20 million pills seized • More than 100 illicit drug outlets closed • 33 arrests Storm I 8 5 months 2008 • 186 raids • Estimated value: $6.65 million • 27 arrests Mamba III 5 2 months 2010 • 200,000 pills seized • 375 premises targeted • 120 police cases opened, 78 prosecutions, 34 convictions Mamba II 3 1 month 2009 • Thousands of tablets seized • 270 premises targeted • 83 police cases opened • 4 convictions Mamba I 2 1 week 2008 • More than 100 different products seized • 262 premises inspected • 82 police cases opened Cobra 7 1 week 2011 • 5,500 boxes of medicines seized • More than 100 arrests SOURCE: Adapted from Interpol, 2010a,b, 2011b. CASE REPORTS AND CONVENIENCE SAMPLES Scientific literature contains valuable reports of drug contamination; often clinicians uncover fake drugs in the course of their practice. News- papers, court documents, and other gray literature sources also contain valuable information about drug quality lapses. Convenience surveys and case reports can be useful for identifying a problem in particular product lines or building momentum for further research. The following brief analysis of convenience surveys and case reports in- dicates that drug quality lapses happen around the world. In countries with strong regulatory systems, the problems are often confined to gray market purchases of the so-called lifestyle drugs, medicines for erectile dysfunction and cosmetic conditions. In poor countries a wide range of products are compromised, including most essential medicines.

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THE MAGNITUDE OF THE PROBLEM 95 Key Findings and Conclusions •  ase studies and postmortem investigations generate interest in sub- C standard and falsified drugs. These reports can drive epidemiological research. •  onvenience surveys suggest serious problems with antimicrobial C drug quality in low- and middle-income countries, and especially with antimalarial quality in sub-Saharan Africa and Southeast Asia. Case Reports A great deal of literature on falsified and substandard drugs describes problems that emerge only after patients have been harmed (Ravinetto et al., 2012). These reports do not set out to comment on the regional burden of poor drug quality or trends in compromised products, but they are useful for other reasons. Many of these stories receive significant media attention, encouraging public interest in the problem. Case studies also give under- standing of the social and environmental conditions that foster problems with falsified and substandard drugs (Pew, 2012). Patient case studies are a common type of incidental investigation. For example, the rapid deterioration and death of a Burmese patient with uncomplicated malaria triggered a drug analysis that found the medicines used to treat him were both falsified and substandard (Newton et al., 2006). A postmortem investigation in a previously healthy, 58-year-old Canadian woman found that her death was from acute metal poisoning from a variety of falsified and substandard drugs, many of them antianxiety and antide- pressive medications she bought from the internet (Solomon, 2007). Individual deaths can trigger drug quality investigations; mass causali- ties are clearly more likely to rouse suspicion. Chapter 2 describes one such incident, when a Panamanian physician reported on a spike in cases of acute renal failure, accompanied by neurological dysfunction, abdominal symptoms, urinary irregularities, anorexia, and fatigue (Rentz et al., 2008). A case-control investigation found diethyelene glycol poisoning to be the cause of the outbreak (Rentz et al., 2008). Later investigations, including a Pulitzer Prize–winning New York Times series, implicated falsified ingre- dients from China in an international poisoning crisis (Bogdanich, 2007; Rentz et al., 2008). Newspaper reports and other gray literature sources also contain a wealth of information about drug quality problems. Monitoring this litera- ture is a valuable way to follow what drugs are compromised and where. The U.S. Pharmacopeia’s Media Reports on Medicine Quality Focusing on

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126 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS TABLE 3–7 Reports of Poor-Quality Antimalarial Drugs by Region in Southeast Asia and Sub-Saharan Africa, 1999-2011 Date of Sample Location Collection Drug Tested Method of Testing Southeast Asia Newton et al. Cambodia, Laos, 1999–2000 Artesunate HPLC, colorimetric (2001) Myanmar (Burma), testing (fast red Thailand, Vietnam dye), packaging analysis Newton et al. Cambodia, 1999–2005 Artesunate HPLC, colorimetric (2008) Laos, Myanmar, testing (fast red Thailand-Myanmar dye), packaging border, Vietnam analysis Dondorp et al. Cambodia, Laos, 2002–2003 Artesunate, HPLC, colorimetric (2004) Myanmar, Thailand, artemether, testing (fast red Vietnam dihydroartemisinin, dye), packaging mefloquine analysis Lon et al. Cambodia 2003 Artesunate, quinine, HPLC, thin layer (2006) chloroquine, chromatography, tetracycline, packaging mefloquine analysis, disintegration analysis Sengaloundeth Laos 2003 Artesunate HPLC, colorimetric et al. (2009) testing (fast red dye), mass spectroscopy, pollen analysis, X-ray diffraction, packaging analysis U.S. Pharmacopeia China 2004 Artesunate, quinine, HPLC, thin layer (2004) chloroquine, chromatography, sulfadoxine- visual inspection, pyrimethamine, dissolution mefloquine analysis Bate et al. India 2008–2009 Chloroquine Thin layer (2009) chromatography, disintegration analysis Sub-Saharan Africa Ogwal-Okeng JO Uganda 2001 Chloroquine tablets HPLC et al. and injections (2003) Basco et al. Cameroon 2001 Chloroquine, Colorimetric (2004) quinine, test, thin layer sulfadoxine- chromatography pyrimethamine Amin et al. Kenya 2002 Sulfadoxine- HPLC, dissolution (2005) pyrimethamine, tests amodiaquine

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THE MAGNITUDE OF THE PROBLEM 127 Samples That Failed Testing Total Sampling Sample Chemical Packaging Obtained From Technique Tested Assay Analysis Tests Falsified* Private Convenience 104 39/104 (38%)† 31/84 (38%) 39/104 (38%) pharmacies and outlets Private Convenience 391 196/391 (50%) 195/391 (50%) 195/391 (50%) pharmacies and randomly‡ and outlets Public and Convenience 303 103/303 (34%); 99/303 (33%) 99/303 (33%) private 99/103 (96)† pharmacies and outlets and facilities Public and Convenience 451 122/451 (27%); 72/111 (65%) 88/111 (79%)§ private 30/122 (25%)† pharmacies, and outlets and facilities Private Stratified 30 27/30 (90%) 26/30 (87%) 27/30 (90%) pharmacies random and outlets sampling NS Convenience 39 2/39 (5%)† Not tested 2 (5%) Private Systematic 119 8/119 (7%) Not tested NA pharmacies random and outlets sampling Private and Convenience 92 57/92 (62%) Not tested NA public outlets Private Convenience 284 112/284 (39%) Not tested 49/284 (18%) pharmacies sampling only from various vendors Public and Convenience 116 47/116 (41%) Not tested NA private outlets continued

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128 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS TABLE 3–7 Continued Date of Sample Location Collection Drug Tested Method of Testing Thoithi et al. Kenya 2001–2005 Artemether, Tests of uniformity (2008) dihydroartemisinin, of weight, quinine, content of active sulfadoxine- pharmaceutical pyrimethamine, ingredient, amodiaquine dissolution Atemnkeng et al. Kenya and 2004 Artemether, HPLC with (2007) Democratic arteether, European Republic artesunate, Pharmacopoeia of Congo dihydroartemisinin standards Tipke et al. Burkina Faso 2006 Artesunate, Packaging (2008) artemether analysis, lumefantrine, disintegration quinine, analysis, chloroquine, colorimetric sulfadoxine- tests, thin layer pyrimethamine, chromatography, amodiaquine ultraviolet-visible spectroscopy U.S. Pharmacopeia Madagascar, 2008 Artermisinin- Compendial (2009) Senegal, Uganda combination quality testing treatment, according to U.S. sulfadoxine- Pharmacopeia pyrimethamine standards WHO Cameroon, 2008 Artermisinin- Compendial (2011) Ethiopia, Ghana, combination quality testing Kenya, Nigeria, treatment, according to U.S. Tanzania, sulfadoxine- Pharmacopeia pyrimethamine standards Kibwage Kenya Not provided Sulfadoxine- Dissolution (2005) pyrimethamine analysis Jande et al. Tanzania Not provided Sulfadoxine- Dissolution (2006) pyrimethamine analysis Taylor et al. Nigeria Not provided Quinine, HPLC with British (2001) choroquine, Pharmacopoeia, sulfadoxine- dissolution pyrimethamine, analysis proguanil Smine et al. Senegal Not provided Choroquine, U.S. Pharmacopeia (2002) sulfadoxine- standards pyrimethamine for active pharmaceutical ingredient testing Minzi et al. Tanzania Not provided Sulfadoxine- HPLC, dissolution (2003) pyrimethamine, tests amodiaquine

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THE MAGNITUDE OF THE PROBLEM 129 Samples That Failed Testing Total Sampling Sample Chemical Packaging Obtained From Technique Tested Assay Analysis Tests Falsified* Public and Convenience 41 11/41 (27%) Not tested NA private outlets Randomly, Convenience 24 9/24 (38%) Not tested NA from both sampling of public and different forms private of drug pharmacies or outlets Private Convenience 77 32/77 (42%); 28/77 (38%) 29/77 (38%) and public 1/32 (3%)† pharmacies or outlets Private Convenience 197 64/197 (32%) Not tested NA and public pharmacies and outlets Public and Convenience 267 72/267 (27%) Not tested NA private outlets Public and Convenience 33 23/33 (69%) Not tested NA private outlets Public and Convenience 9 5/9 (55%) Not tested NA private outlets Private Random 284 119/284 (42%) Not tested NA and public pharmacies and outlets Public and Random 27 15/27 (56%) Not tested NA private outlets Public and Convenience 33 10/33 (30%) Not tested NA private outlets continued

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130 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS TABLE 3–7 Continued Date of Sample Location Collection Drug Tested Method of Testing Maponga Gabon, Ghana, Not provided Choroquine, HPLC, dissolution et al. Kenya, Mali, sulfadoxine- analysis, drug- (2003) Mozambique, pyrimethamine specific assays Sudan, Zimbabwe Gaudiano Angola, Burundi, Not provided Quinine, HPLC with U.S. et al. Congo choroquine, Pharmacopeia (2007) sulfadoxine- standards, pyrimethamine, uniformity of mass, mefloquine disintegration analysis Aina et al. Nigeria Not provided Choroquine British (2007) tablets, syrups, and Pharmacopoeia injections dissolution tests, active pharmaceutical ingredient assay, disintegration tests Kaur et al. Tanzania Not provided Artemisnins, HPLC and (2008) quinine, antifolates, dissolution sulfadoxine- analysis with U.S. pyrimethamine, Pharmacopeia amodiaquine standards Bate et al. Ghana, Kenya, Not provided Artesunate, Thin layer (2008) Nigeria, Rwanda, artemether, chromatography Tanzania, Uganda dihydroartermisinin, or dissolution artemether- analysis lumefantrine, sulfadoxine- pyrimethamine, mefloquine, amodiaquine Ofori-Kwakye Ghana Not provided Artesunate Colorimetric tests, et al. (2008) disintegration tests, European Union Pharmacopoeia standards Onwujekwe Nigeria Not provided Artesunate, HPLC and et al. (2009) dihydroartemisinin, dissolution chloroquine, analysis with U.S. quinine, Pharmacopeia sulfadoxine- standards pyrimethamine

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THE MAGNITUDE OF THE PROBLEM 131 Samples That Failed Testing Total Sampling Sample Chemical Packaging Obtained From Technique Tested Assay Analysis Tests Falsified* Private Convenience 278 5–100%¶ Not tested NA and public pharmacies and outlets Mainly small, Convenience 28 16/28 (57%); Not tested 1/28 (4%) private 1/16 (6%)† pharmacies and outlets Public outlet Convenience 32 19/32 (59%) Not tested NA Private Random 301 38/301 (12%) Not tested NA and public pharmacies and outlets Private Convenience 210 73/210 (35%) Not tested NA pharmacies and outlets Public and Convenience 17 14/17 (82%) Not tested NA private outlets Private Stratified 225 60/225 (27%) Not tested NA and public random pharmacies sampling and outlets continued

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132 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS TABLE 3–7 Continued Date of Sample Location Collection Drug Tested Method of Testing Newton et al. Burkina Faso, 2002–2010 Artesunate, HPLC, mass (2011) Chad, Cameroon, dihydroartemisinin, spectroscopy, D.R. Congo, Ghana, dihydroartemisinin- pollen analysis, Kenya, Nigeria, piperaquine X-ray diffraction, Rwanda, Senegal artemether- packaging analysis lumefantrine, artemether- amodiaquine, amodiaquine, halofantrine NOTE: DFID = Data are n/N (%), unless otherwise indicated. Samples failing chemical assay analysis might have failed packaging analysis; HPLC = high-perfomance liquid chromatography; NA = not applicable; NS = not specified. * Falsified is used as a synonym for counterfeit. † Samples with no active pharmaceutical ingredient.

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THE MAGNITUDE OF THE PROBLEM 133 Samples That Failed Testing Total Sampling Sample Chemical Packaging Obtained From Technique Tested Assay Analysis Tests Falsified* Pharmaceutical Convenience 59 35/59 (59%); 26/36 (72%) 14/59 (24%) companies, 11/35 (31%)*¶ private and public pharmacies ‡ 115 samples from Laos were randomly selected. § Only tetracycline, quinine, and artesunate were tested. ¶ Varies substantially by drug and country; not included in analysis. SOURCE: Nayyar et al., 2012. Reprinted from the Lancet with permission from Elsevier.

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