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Substandard and falsified medicines are harmful to patients, causing prolonged illness, side effects, and preventable deaths. Moreover, they have an impact on the health system and society more broadly by leading to additional care, higher disease burden, productivity losses and loss of trust in health care. Models that estimate the health and economic impacts of substandard and falsified medicines can be useful for regulators to contextualize the problem and to make an economic case for solutions. Yet these models have not been systematically catalogued to date. We reviewed existing models that estimate the health and economic impact of substandard and falsified medicines to describe the varying modeling approaches and gaps in knowledge. We compared model characteristics, data sources, assumptions, and limitations. Seven models were identified. The models assessed the impact of antimalarial (n = 5) or antibiotic (n = 2) quality at a national (n = 4), regional (n = 2), or global (n = 1) level. Most models conducted uncertainty analysis and provided ranges around potential outcomes. We found that models are lacking for other medicines, few countries’ data have been analyzed, and capturing population heterogeneity remains a challenge. Providing the best estimates of the impact of substandard and falsified medicines on a level that is actionable for decision-makers is important. To enable this, research on the impact of substandard and falsified medicines should be expanded to more medicine types and classes and tailored to more countries that are affected, with greater specificity.

Substandard and falsified pharmaceuticals, prevalent in low- and middle-income countries, substantially increase levels of morbidity, mortality and drug resistance. Regulatory agencies combat this problem using post-market surveillance by collecting and testing samples where consumers purchase products. Existing analysis tools for post-market surveillance data focus attention on the locations of positive samples. This paper looks to expand such analysis through underutilized supply-chain information to provide inference on sources of substandard and falsified products. We first establish the presence of unidentifiability issues when integrating this supply-chain information with surveillance data. We then develop a Bayesian methodology for evaluating substandard and falsified sources that extracts utility from supply-chain information and mitigates unidentifiability while accounting for multiple sources of uncertainty. Using de-identified surveillance data, we show the proposed methodology to be effective in providing valuable inference.

Monitoring the quality of medicines plays a crucial role in an integrated medicines quality assurance system. In a publicly available medicines quality database (MQDB), the U.S. Pharmacopeial Convention (USP) reports results of data collected from medicines quality monitoring (MQM) activities spanning the period of 2003-2013 in 17 countries of Africa, Asia, and South America. The MQDB contains information on 15,063 samples collected and tested using Minilab ® screening methods and/or pharmacopeial methods. Approximately 71% of the samples reported came from Asia, 23% from Africa, and 6% from South America. The samples collected and tested include mainly antibiotic, anti- malarial, and antituberculosis medicines. A total of 848 samples, representing 5.6% of total samples, failed the quality test. The failure proportion per region was 11.5%, 10.4%, and 2.9% for South America, Africa, and Asia, respectively. Eighty-one counterfeit medicines were reported, 86.4% of which were found in Asia and 13.6% in Africa. Additional analysis of the data shows the distribution of poor-quality medicines per region and by therapeutic indication as well as possible trends of counterfeit medicines. testing, and reporting. The testing involves field screening tests, verification tests to confirm results obtained in the field by repeating a screening test on failed and doubtful samples, and a pharmacopeial or validated method to confirm the results of the verification test. This methodology is referred to as the three-level approach for monitoring the quality of medicines available in the market. 12 In this paper, data currently available in MQDB, plus new data not yet publicly available, were analyzed with a focus on global and regional data, and the distribution of therapeu- tic classes, their failure proportions, the presence of counter- feit medicines, and possible trends were explored. Three out of the 17 total countries examined for this paper do not pub- licly release their results in the database; however, their data were included in the global and regional analyses.

Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines.

ObjectivesIn this paper we discuss the main ethical challenges related to the conduct of medicine quality surveys and make suggestions on how to address them. MethodMost evidence-based information regarding medicine quality derives from surveys. However, existing research ethical guidelines do not provide specific guidance for medicine quality surveys. Hence, those conducting surveys are often left wondering how to judge what counts as best practice. A list of the main ethical challenges in the design and conduct of surveys is presented. Results and conclusionsIt is vital that the design and conduct of medicine quality surveys uphold moral and ethical obligations and analyse the ethical implications and consequences of such work. These aspects include the impact on the local availability of and access to medicines; the confidentiality and privacy of the surveyors and the surveyed; questions as to whether outlet staff personnel should be told they are part of a survey; the need of ethical and regulatory approvals; and how the findings should be disseminated. Medicine quality surveys should ideally be conducted in partnership with the relevant national Medicine Regulatory Authorities. An international, but contextually sensitive, model of good ethical practice for such surveys is needed. ObjectifsIdentifier et discuter les principaux enjeux ethiques lies a la conduite des surveillances et formuler des suggestions sur la facon de les aborder. MethodeLa plupart des informations fondees sur des preuves en ce qui concerne la qualite des medicaments decoule des enquetes. Cependant, les directives ethiques de recherche existantes ne fournissent pas d'indications precises pour les enquetes sur la qualite de la medecine. Par consequent, ceux menant des enquetes sont souvent laisses a se demander comment juger ce qui compte comme la meilleure pratique. Une liste des principaux defis ethiques dans la conception et la conduite des enquetes est presentee. Resultats et conclusionsIl est essentiel que la conception et la conduite des enquetes sur la qualite de la medecine respectent les obligations morales et ethiques et analysent les implications ethiques et les consequences d'un tel travail. Celles-ci sont: l'impact sur la disponibilite locale et l'acces aux medicaments, la confidentialite et la protection de la vie privee des enqueteurs et des enquetes, des questions quant a savoir si les membres du personnel de sortie doivent etre informes quils font partie d'une enquete, la necessite d'approbations reglementaires et d'ethique et la facon dont les resultats devraient etre diffuses. Les enquetes sur la qualite de la medecine devraient idealement etre menees en partenariat avec les autorites relevantes de reglementation des medicaments nationaux. Un modele international, mais contextuellement sensible, de bonne pratique ethique pour ces enquetes est necessaire. ObjetivosIdentificar y discutir los principales retos eticos relacionados con la realizacion de encuestas y hacer sugerencias sobre la forma de abordarlas. MetodoLa mayor parte de la informacion basada en la evidencia en lo que respecta a la calidad de los medicamentos se obtiene a traves de encuestas. Sin embargo, las guias eticas de investigacion existentes no proveen una guia especifica para las encuestas de calidad de medicamentos. Por lo tanto, aquellos que llevan a cabo las encuestas a menudo no saben como definir lo que se considera como la mejor practica. Aqui se presenta una lista de los principales retos eticos en el diseno y en la realizacion de encuestas. Resultados y conclusionesEs vital que el diseno y el pase de encuestas de calidad de medicamentos apoyen obligaciones eticas y morales, asi como el analisis de las implicaciones y las consecuencias eticas de dicho trabajo. Estas son: el impacto sobre la disponibilidad local de y el acceso a las medicinas; la confidencialidad y la privacidad de los encuestados y encuestadores; preguntas sobre si los trabajadores del punto de entrega deberian ser avisados de que estan formando parte de un estudio; la necesidad de aprobaciones eticas y regulatorias; y como diseminar los hallazgos obtenidos. Las encuestas sobre la calidad de los medicamentos deberian idealmente realizarse junto con las autoridades nacionales relevantes en regulacion de medicamentos. Se requiere un modelo internacional, pero contextualmente sensible, de buenas practicas eticas.

The availability of poor quality medi-cines – i.e. medicinal products that are substandard, spurious, falsely labelled, falsified or counterfeit, as defined by the World Health Organization (WHO) – has become an issue of public health concern. Such medicines can jeopardize patient safety, lead to treatment failure and to the development of drug resis-tance

Regulators from countries at all levels of income struggle to protect the public from the dangers of poor-quality (counterfeit and substandard) medicines. In particular countries with limited resources are at higher risk because of weak regulations, insufficient personnel, or laboratories with poor infrastructure and a lack of equipment required to perform quality control analysis. A systematic approach is needed to address these gaps. A stepwise process was used to design medicine quality monitoring programs in numerous countries in Africa, South America, and Southeast Asia. The experience gained in these countries resulted in the development of the Three-level Approach for performing quality control of medicines throughout the supply chain. The approach consists of three successive, complementary, and increasingly complex levels of analysis: The first level includes visual and physical inspection to assess package and insert conditions and information as well as the physical characteristics of the actual medicines. The second level consists of rapid analytical tests that assess a limited number of quality attributes and can easily be performed in the field by trained personnel. The third level involves quality control testing according to the product’s registration specifications and is performed in an appropriate laboratory setting by experienced and trained analysts. The Three-level Approach offers regulators in limited resource countries, a cost-effective high-throughput methodology for quality monitoring that produces valid and trustworthy results. The approach strengthens medicines quality assurance systems by allowing better regulation of the pharmaceutical market, which ultimately reduces the prevalence of poor-quality medicines.

Cambodia's Ministry of Health and the Department of Drugs and Food have been actively working to reduce the amount of poor quality medicines circulating in the pharmaceutical sector since fake mefloquine and artesunate were first found in 1998. From 2005-2012, legal private sector facilities and illegal outlets in twelve Cambodian provinces were targeted for routine surveillance of medicine quality through sample collection and testing of various anti-infective medicines, the majority of which were anti-malarials and anti-biotics. The Medicine Quality Monitoring program samples from the field were analyzed through a three level approach including field and advanced laboratory testing. 4,381 medicines were collected and tested from 2005-2012; 106 have failed quality testing resulting in an overall failure rate of 2.4%. 28 of the failed samples (26.4%) were counterfeit. The most commonly found counterfeit medicines were chloroquine, artesunate, mefloquine, ampicillin and penicillin. Cambodia has closed over 99% of illegal pharmacy outlets through the Inter-Ministerial Committee to Fight against Counterfeit & Substandard Medicines (IMC) by the end of November 2011. In the past, a lack of resources as well as coordination among the various ministries was identified as a major barrier in combating the presence of poor quality medicines. With financial support from USAID, PMI, and other donors, paired with the technical support from the U.S. Pharmacopeial Convention Promoting the Quality of Medicines program, the IMC developed an action plan to significantly reduce the number of substandard and counterfeit medicines. Based on the data shown, the plan has been successful in reducing the failure rates of samples collected in Cambodia from a high of 7.4% in 2006 to a low of 0.7% in 2011. Continued efforts to monitor and actively ensure the quality of medicines in Cambodia will be required to maintain these low rates; sustainability of these efforts is critical.

This study examined the prevalence, availability, and use of antimalarial medicines (AMLs) along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in six Thai provinces and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for verification testing. For the second part of the study, face-to-face interviews were conducted with members of randomly selected households and the staff of health facilities in villages with the highest malaria incidence to find out where they acquired their AMLs and which were used most frequently. The results of quality testing showed an overall failure rate of 1% (7 of 709 samples) for active pharmaceutical ingredients (API); however, the API failure rate varied from 0.0% to 2.2% by location and the overall failure rates of samples by province varied from 0.0% to 3.4%. A total of 97.9% (n = 272) of respondents had taken AMLS. The most commonly used medicines were primaquine (30% of respondents), chloroquine (15.8%), artesunate+mefloquine (12%), and quinine (10%). Most respondents (97.9%) had received medications from public hospitals or malaria clinics.

The prevalence, availability, and use of antimalarial medicines (AMLs) were studied in six Cambodian provinces along the Thai-Cambodian border. The study was divided into two parts: the first looked at the quality of AMLs available in Pursat, Pailin, Battambang, Bantey Meanchey, Oddar Meanchey, and Preah Vihear and the second obtained information about the availability and use of AMLs. A randomized sampling methodology was used to select locations and collect samples, which were screened using Global Pharma Health Fund (GPHF) Minilabs. A subset of samples was sent to quality control laboratories for confirmatory testing. For the second part of the study, face-to-face interviews were conducted using standardized surveys with members of randomly selected households and staff of health facilities in the villages with highest malaria incidence to find out where they acquired their AMLs and which were most frequently used. The results showed an overall failure rate of 12.3% (n = 46 of 374 total AML samples). The causes of medication sample failure were low active pharmaceutical ingredient (API) content, failed dissolution properties, and unacceptably high levels of impurities. A total of 86.2% of survey respondents (n = 1,648 of 1,912) reported a member of their household having malaria in the previous year. The most commonly used medicines were paracetamol (67.1% of respondents), Malarine (A+M co-blistered, 28.6%), artesunate + mefloquine co-blistered (public sector product, 17.3%), quinine (16.7%), and artesunate monotherapy (11.9%). Health staff typically prescribed co-blistered artesunate plus mefloquine in the public sector (67.8%), the artesunate plus mefloquine "social marketing" product from Population Services International (PSI), Malarine (50.3%) in the private sector, artemether (49.7%), chloroquine (39%) and paracetamol (72.9%) to reduce fever.

Background Since 1998 the serious public health problem in South East Asia of counterfeit artesunate, containing no or subtherapeutic amounts of the active antimalarial ingredient, has led to deaths from untreated malaria, reduced confidence in this vital drug, large economic losses for the legitimate manufacturers, and concerns that artemisinin resistance might be engendered. Methods and Findings With evidence of a deteriorating situation, a group of police, criminal analysts, chemists, palynologists, and health workers collaborated to determine the source of these counterfeits under the auspices of the International Criminal Police Organization (INTERPOL) and the Western Pacific World Health Organization Regional Office. A total of 391 samples of genuine and counterfeit artesunate collected in Vietnam (75), Cambodia (48), Lao PDR (115), Myanmar (Burma) (137) and the Thai/Myanmar border (16), were available for analysis. Sixteen different fake hologram types were identified. High-performance liquid chromatography and/or mass spectrometry confirmed that all specimens thought to be counterfeit (195/391, 49.9%) on the basis of packaging contained no or small quantities of artesunate (up to 12 mg per tablet as opposed to ∼ 50 mg per genuine tablet). Chemical analysis demonstrated a wide diversity of wrong active ingredients, including banned pharmaceuticals, such as metamizole, and safrole, a carcinogen, and raw material for manufacture of methylenedioxymethamphetamine (‘ecstasy'). Evidence from chemical, mineralogical, biological, and packaging analysis suggested that at least some of the counterfeits were manufactured in southeast People's Republic of China. This evidence prompted the Chinese Government to act quickly against the criminal traders with arrests and seizures. Conclusions An international multi-disciplinary group obtained evidence that some of the counterfeit artesunate was manufactured in China, and this prompted a criminal investigation. International cross-disciplinary collaborations may be appropriate in the investigation of other serious counterfeit medicine public health problems elsewhere, but strengthening of international collaborations and forensic and drug regulatory authority capacity will be required., Paul Newton and colleagues' international, collaborative study found evidence that counterfeit artesunate was being manufactured in China, which prompted a criminal investigation., Editors' Summary Background Malaria is one of the world's largest public health problems, causing around 500 million cases of illness and at least one million deaths per year (the estimates vary widely). The most serious form of malaria is caused by the parasite Plasmodium falciparum, which has become resistant to multiple drugs that had previously been the cornerstones of antimalarial regimens. One group of drugs for treating malaria, the artemisinin therapies including artesunate, are based upon a Chinese herb called qinghaosu; these have now become vital to the treatment of P. falciparum malaria. But counterfeit artesunate, containing none or too little (“subtherapeutic levels”) of the active ingredient, is a growing problem especially in South and East Asia. Fake artesunate is devastating for malaria control: it causes avoidable death, reduces confidence in the drug, and takes away profit from legitimate manufacturers. Of major concern also is the potential for subtherapeutic counterfeit artesunate to fuel the parasite's resistance to the artemisinin group of drugs. Previous estimates have suggested that between 33% and 53% of artesunate tablets in mainland South East Asia are counterfeit. In this paper the authors report on an unprecedented international collaboration and criminal investigation that attempted to quantify and source counterfeit artesunate among some of the most malarious countries in Asia. Why Was This Study Done? Previous reports have identified the problem of fake artesunate, but as of yet there have been few reports on the potential solutions. Concerned health workers and scientists, the regional World Health Organization (WHO) office and the International Criminal Police Organization (INTERPOL) got together to discuss what could be done in May 2005 when it became clear the counterfeit artesunate situation was worsening in the Greater Mekong Sub-Region of South East Asia (comprising Cambodia, Lao People's Democratic Republic, Myanmar, Thailand, Vietnam, and Yunnan Province in the People's Republic of China). Their subsequent investigation combined the goals and methods of a range of concerned parties—police, scientists, and health workers—to identify the source of counterfeit artesunate in South East Asia and to supply the evidence to help arrest and prosecute the perpetrators. What Did the Researchers Do and Find? The researchers conducted forensic analyses of samples of genuine and counterfeit artesunate. They selected these samples from larger surveys and investigations that had been conducted in the region beginning in the year 2000. Genuine samples were supplied by a manufacturer to provide a comparator. The authors examined the physical appearance of the packages and subjected the tablets to a wide range of chemical and biological tests that allowed an analysis of the components contained in the tablets. When comparing the collected packages and tablets against the genuine samples, the researchers found considerable diversity of fake artesunate in SE Asia. Sixteen different fake hologram types (the stickers contained on packages meant to identify them as genuine) were found. Chemical analysis revealed that all tablets thought to be fake contained no or very small quantities of artesunate. Other ingredients found in the artesunate counterfeit tablets included paracetamol, antibiotics, older antimalarial drugs, and a range of minerals, and there were a variety of gases surrounding the tablets inside the packaging. Biological analyses of pollen grains inside the packaging suggested that the packages originated in the parts of South East Asia along the Chinese border. What Do these Findings Mean? The results were crucial in helping the authorities establish the origin of the fake artesunate. For example, the authors identified two regional clusters where the counterfeit tablets appeared to be coming from, thus flagging a potential manufacturing site or distribution network. The presence of wrong active pharmaceutical ingredients (such as the older antimalarial drugs) suggested the counterfeiters had access to a variety of active pharmaceutical ingredients. The presence of safrole, a precursor to the illicit drug ecstasy, suggested the counterfeits may be coming from factories that manufacture ecstasy. And the identification of minerals indigenous to certain regions also helped identify the counterfeits' origin. The researchers concluded that at least some of the counterfeit artesunate was coming from southern China. The Secretary General of INTERPOL presented the findings to the Chinese government, which then carried out a criminal investigation and arrested individuals alleged to have produced and distributed the counterfeit artesunate. The collaboration between police, public health workers and scientists on combating fake artesunate is unique, and provides a model for others to follow. However, the authors note that substantial capacity in forensic analysis and the infrastructure to support collaborations between these different disciplines are needed. Additional Information. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050032. The World Health Organization in 2006 created IMPACT—International Medical Products Anti-Counterfeiting Taskforce—with the aim of forging international collaboration to seek global solutions to this global challenge and in raising awareness of the dangers of counterfeit medical products. The task force membership includes international organizations, nongovernmental organizations, enforcement agencies, pharmaceutical manufacturers' associations, and drug and regulatory authorities. IMPACT's Web site notes that trade in counterfeit medicines is widespread and affects both developed and developing countries but is more prevalent in countries that have weak drug regulatory systems, poor supply of basic medicines, unregulated markets, high drug prices and/or significant price differentials. IMPACT holds international conferences and maintains a rapid alert system for counterfeit drugs. The drug industry's anticounterfeit organization, Pharmaceutical Security Institute, works to develop improved systems to identify the extent of the counterfeiting problem and to assist in coordinating international inquiries. Its membership includes 21 large pharmaceutical companies. The Web site of David Pizzanelli, a world expert on security holography, contains a PowerPoint presentation co-authored by Paul Newton that illustrates the different types of fake holograms found on fake artesunate packages, and their implications for artemisinin resistance (http://www.pizzanelli.co.uk/content/artesunate.html).

In PLoS Medicine, volume 3, issue 6: DOI: 10.1371/journal.pmed.0030197 In the first paragraph of the section The Epidemic of Counterfeit Artesunate in Southeast Asia, the sentence “Counterfeit artesunate continues to circulate on a vast scale in mainland Southeast Asia, where between 38% and 52% of “artesunate” blister packs sampled contain no active ingredient [1–5]” should be “Counterfeit artesunate continues to circulate on a vast scale in mainland Southeast Asia, where between 38% and 53% of “artesunate” blister packs sampled contain no active ingredient [1–5].”

Fake artesunate could compromise the hope that artemisinin-based combination therapy offers for malaria control in Africa and Asia.

This meeting report presents the key findings and discussion points of a 1-day meeting entitled 'Fake anti-malarials: start with the facts' held on 28th May 2015, in Geneva, Switzerland, to disseminate the findings of the artemisinin combination therapy consortium's drug quality programme. The teams purchased over 10,000 samples, using representative sampling approaches, from six malaria endemic countries: Equatorial Guinea (Bioko Island), Cambodia, Ghana, Nigeria, Rwanda and Tanzania. Laboratory analyses of these samples showed that falsified anti-malarials (