Counterfeit medicines: relevance, consequences and strategies to combat the global crisis

Abstract Counterfeiting of medicines, also known as "falsification" or "adulteration", is the process in which the identity, origin, or history of genuine medicines are intentionally modified. Currently, counterfeit medicines are a global crisis that affects and is mostly caused by developing countries in Asia, Africa and Latin America. These countries lack strict law enforcement against this practice and have low-income populations with medicinal needs. Lately, the crisis has escalated, impacting developed countries as well, e.g., the US and the EU, mainly via the Internet. Despite this extension, some current laws aim to control and minimize the crisis' magnitude. Falsification of medicines maintains an illegitimate supply chain that is connected to the legitimate one, both of which are extremely complex, making such falsification difficult to control. Furthermore, political and economic causes are related to the crisis' hasty growth, causing serious consequences for individuals and public health, as well as for the economy of different countries. Recently, organizations, technologies and initiatives have been created to overcome the situation. Nevertheless, the development of more effective measures that could aggregate all the existing strategies into a large functioning network could help prevent the acquisition of counterfeit medicines and create awareness among the general population.

Criminal Action Against Drug Counterfeiters: Assessment of the FDA Office of Criminal Investigation Database 2016 Through 2021.

OBJECTIVE: The objective of this study was to describe law enforcement oversight of counterfeit drugs by the Food and Drug Administration (FDA) in the United States from 2016 through 2021. METHODS: The FDA Office of Criminal Investigation database with hyperlinked press releases of enforcement actions was used to identify legal action against drug counterfeiters. Incidences of counterfeit drugs sold via Internet, how often they were obtained without a prescription, the most prevalent counterfeit drugs, the countries where counterfeit operations occurred, and the scale of counterfeit operations were assessed. RESULTS: There were 130 unique enforcement actions against counterfeiting organizations and individuals. Overall, 64.6% of enforcement actions involved counterfeit products sold over the Internet, in 84.6% of actions counterfeit medications could be obtained without a prescription, and in 33.1% of actions the products were sold as dietary supplements. Sexual dysfunction, opioid, stimulant, anabolic muscle building, benzodiazepine, and dermatologic drugs were most counterfeited. China was the most prevalent country to produce counterfeit drugs followed by India, Turkey, Pakistan, and Russia. Counterfeiting operations were large with tens of millions of pills and hundreds of millions of dollars in sales. Health outcomes for counterfeit drugs were rarely discussed in the press releases and not all press releases had data for each parameter of interest. CONCLUSION AND RELEVANCE: This is the first report assessing enforcement actions against drug counterfeiters from the FDA Office of Criminal Investigation. The FDA is actively involved in identifying and prosecuting counterfeit drug rings, but the number of enforcement actions is smaller than the size of the problem.

Dermatologic Consequences of Substandard, Spurious, Falsely Labeled, Falsified, and Counterfeit Medications.

This article explores dermatologic consequences of substandard, spurious, falsely labeled, falsified, and counterfeit (SSFFC) pharmaceutical products. Many of these SSFFC products are neither safe nor effective, and are more likely to cause adverse events than the proper preparations. These products also affect the health of populations by generating drug-resistant pathogens and failing to control the spread of disease. This article reviews classification systems for fraudulent medications, provides a general overview of medical and public health problems associated with substandard medications, provides examples of dermatologic consequences of each category, and presents recommended steps to take when clinicians encounter suspected SSFFC products.

The plague of unexpected drug recalls and the pandemic of falsified medications in cardiovascular medicine as a threat to patient safety and global public health: A brief review.

Valsartan, losartan, and irbesartan, are widely used in the treatment strategies of cardiovascular medicine diseases, including hypertension and heart failure. Recently, many formulations for the aforementioned diseases contained active pharmaceutical ingredients and had been abruptly recalled from the market due to safety concerns mainly associated with unwanted impurities - nitrosamines, which are highly carcinogenic substances accidentally produced during manufacturing. Along with cardiovascular medications, formulations containing ranitidine were also recalled from the market. This poses a particular threat to public health due to the non-prescription status of these drugs. Regulatory authorities, including the Food and Drug Administration and European Medicines Agency among others, have taken action to minimize patient risk and improve the manufacturing quality as well as re-checking current guidelines and recommendations. While these steps are necessary to avoid further recalls, authorities should remember the growing concerns of patients regarding the safety and efficacy of pharmacotherapy. Apart from the genuine manufacturing mistakes mentioned above, falsified and counterfeit medications should be at the heart of global attention. The lack of a well-accepted definition of falsified/counterfeit medications has impeded political and scientific efforts to mitigate risk of this phenomenon. Falsified Medicines Directive should be considered the most pivotal legislation recently enacted to harmonize international cooperation. In summary, one should remember that only international and direct collaboration between patients, stakeholders, and authorities be considered a remedy for a pandemic of falsified medicines and plague of unexpected recalls due to safety concerns.

Acute lead poisoning: a diagnostic challenge in the emergency department.

Acute abdominal pain is a common presentation to the emergency department (ED). Ruling out life-threatening causes and giving pain relief are the most important tasks in ED. We describe a 32-year-old man who presented to ED with abdominal pain and vomiting which was unrelieved by usual doses of analgesic. Extensive investigations revealed no significant abnormalities. On further probing, he admitted taking traditional medications for infertility. The toxicological panel revealed a high blood lead level, leading to a diagnosis of acute lead toxicity. Chelation therapy with D-penicillamine was initiated and the patient's abdominal pain resolved within 4 days.

An overview on performance and image enhancing drugs (PIEDs) confiscated in Italy in the period 2017-2019.

CONTEXT: The illegal market of counterfeit and falsified medicines and supplements containing unlabeled pharmaceuticals is expanding worldwide. They are usually referred to by the term "performance and image enhancing drugs" (PIEDs) and are mainly steroids, stimulants, hormones, and drugs for erectile dysfunction. PIEDs are easily accessible through the online or black markets. We analyzed over 400 such medicines confiscated in Italy in the period 2017-2019, to determine their composition. METHODS: Confiscated products were analyzed by gas chromatography/mass spectrometry and liquid chromatography/high-resolution mass spectrometry, in order to ascertain their composition and to evaluate the correspondence between what was declared on the label and the actual content, or to identify unknown products. RESULTS: The most commonly found substance was anabolic steroids, found in 64% of products, with 11% containing hormone modulators, 6% stimulants, 6% sexual enhancers (mainly sildenafil) and other drugs, including thyroid hormones, melanin stimulators, and vitamins. These substances were often in mixtures. The products were often mislabeled, containing contaminants in addition to the drug declared, or consisted of a drug completely different from the one reported on the label. Fifteen percent of products had a qualitative composition completely different from that declared, while 10% of products showed cross-contamination with other drugs, mainly testosterone esters, probably due to the presence of residues of other drugs in the production line. In addition, 11% of products were not labeled, so their purported composition was unknown. DISCUSSION: PIEDs pose a threat to public health. The main risks are related to the intrinsic toxicity of the substances found, especially when taken without a therapeutic indication. Another issue is related to the mislabeling of the fake medicines, and the poor-quality standard of counterfeit product preparation, with additional risks of the presence of other toxic ingredients or microbial contamination. CONCLUSIONS: The use of counterfeit products is a public health concern, as it constitutes a high risk for consumer health. It is mainly caused by the uncontrolled use of steroids, stimulants, sexual enhancers, and other medicaments, without medical indication or supervision, with variable and unknown compositions and doses, as well as other contaminants as a result of the absence of good manufacturing practices.

Edible unclonable functions.

Counterfeit medicines are a fundamental security problem. Counterfeiting medication poses a tremendous threat to patient safety, public health, and the economy in developed and less developed countries. Current solutions are often vulnerable due to the limited security levels. We propose that the highest protection against counterfeit medicines would be a combination of a physically unclonable function (PUF) with on-dose authentication. A PUF can provide a digital fingerprint with multiple pairs of input challenges and output responses. On-dose authentication can verify every individual pill without removing the identification tag. Here, we report on-dose PUFs that can be directly attached onto the surface of medicines, be swallowed, and digested. Fluorescent proteins and silk proteins serve as edible photonic biomaterials and the photoluminescent properties provide parametric support of challenge-response pairs. Such edible cryptographic primitives can play an important role in pharmaceutical anti-counterfeiting and other security applications requiring immediate destruction or vanishing features.

Experiences With Counterfeit Aesthetic Medical Devices and Injectables: A National Survey.

BACKGROUND: Counterfeit medical devices and injectables have recently garnered interest in the field of aesthetics. Unlike their original counterparts, these counterfeit products have neither been tested nor verified using certified quality control measures. OBJECTIVE: Our study investigated the pervasiveness of counterfeit products in the field as well as the experiences and attitudes of practitioners. MATERIALS AND METHODS: An online survey was distributed to current members of the American Society for Dermatologic Surgery (ASDS) and the American Society for Laser Medicine and Surgery (ASLMS). RESULTS: For medical devices, 37.4% have encountered counterfeits and 20.1% have experienced patients with adverse events from them. For injectables, 41.1% have encountered counterfeits and 39.7% have experienced patients with adverse events from them. Compared with their original, most respondents believe that counterfeits are worse in terms of reliability, safety, and effectiveness. The majority also believe that counterfeits are either very or extremely endangering to patient safety. CONCLUSION: Counterfeit medical devices and injectables are not uncommonly encountered. Overall, practitioners believe counterfeits are endangering patient safety and result in adverse events and think that either stricter rules and regulations or better enforcement of existing regulations is necessary.

Impact of Abuse of Topical Corticosteroids and Counterfeit Cosmetic Products for the Face: Prospective Demographic Study in Basrah City, Iraq.

BACKGROUND: Topical corticosteroids are highly effective compounds that are now widely used in dermatology for the treatment of various autoimmune and inflammatory disorders. Many corticosteroids are misused for diverse indications such as pigmentation, acne, pruritus, fungal or bacterial infections, rashes, and numerous other conditions. These products contain various constituents, most of which have hazards or toxic elements. OBJECTIVE: The aim is to raise awareness among individuals in the city of Basrah, Iraq about the uses and abuses of applying fake products to the face to inform the consumers about potential harmful adverse effects. METHODS: This study was a prospective multi-center clinic questionnaire of a demographic that involved the outpatient dermatology departments at the Al-Basrah teaching hospital and the Abu Al-Khaseeb hospital as well as the private clinics of two dermatology specialists in Basrah. A total of 235 patients with facial dermatoses secondary to the application of topical corticosteroids and counterfeit products or, a mixed formulation, for cosmetic purposes were recruited. RESULTS: Most enrolled patients were female with 10-20 years aged group. The majority applied these products due to friends or pharmacy encouragement. Motivations for the use of these products included: skin fairness, lightening, and general cosmetic. Interestingly, acne and erythema were common whilst, atrophy, dryness, telangiectasia, and hirsutism appear on long- term use only. CONCLUSION: The abuse of counterfeit cosmetic products and topical corticosteroids is in progress and they have adverse health events. There are many causes behind the abuse but the lack of education, lack of restriction, profitable for sellers and low prices are the main.

Veterinary pharmacovigilance in sub-Sahara Africa context: a pilot study of adverse reactions to veterinary medicine in Cameroon.

BACKGROUND: Sub-Saharan African market is highly affected by counterfeit veterinary drugs. Though these counterfeit and non-compliance of drugs can induce adverse effects during their utilization, there is no monitoring system of veterinary medicines. The present pilot study was carried out in Cameroon to identify and describe suspected cases of adverse reactions to veterinary drugs in animals and / or humans as well as inefficacy of veterinary drugs. The methodology involved a descriptive cross-sectional survey of 67 actors in the veterinary medicine sector in Cameroon. RESULTS: A total of 74/120 (62%) cases of suspected adverse effects and or lack of efficacy of veterinary drugs in animals and 46 (38%) cases of adverse reactions in humans were identified. Antiparasitics were the most incriminated therapeutic class in animals (61%) and human (56%). Adverse reactions were reported in dogs (44%) and poultry (24%) while drug inefficacy was most observed in poultry (47%). According to animal health professionals, levamisole (24%) and ivermectin (16%) were identified to be responsible for the adverse effects and that the highest level of inefficacy was most frequently reported for oxytetracycline (29%). The main adverse reactions were systemic (22%), gastrointestinal (20%) and neurological (13%) disorders. CONCLUSION: The results of this study showed that misuse and circulation of poor quality as well as lack of efficacy of veterinary drugs is very common in Cameroon. Adverse reactions were observed in animals and humans. Therefore, the establishment of a national veterinary pharmacovigilance system based on solid legal bases is essential for a continuous assessment of the risks-benefits effects of veterinary drugs marketed in Cameroon.

Cryptopharmaceuticals: Increasing the Safety of Medication by a Blockchain of Pharmaceutical Products.

The future health-care system will contain an ever expanding number of digital elements. The data stored both at a centralized health-care level and at a local, patient level (e.g., on a smartphone) will be core elements when deciding treatment strategies in a health-care scenario with Internet of things-based elements. The current way of manufacturing pharmaceutical products and related existing logistic solutions is not ready for such a revolution. One of the key challenges is cybersecurity and related robust public key infrastructure solution. This work introduces one element of a potential solution at a prototype level: the concept of cryptopharmaceuticals where pharmaceutical products are connected in a patient-specific blockchain of individual dosage units. This technology is based on the concept where each produced dosage unit has a unique information-rich pattern. A proof-of-concept smartphone application was applied to demonstrate the visualization of this blockchain at different levels. This includes the manufacturing of the individualized dosage unit, the patient view for his/her personal blockchain, and integration of these products into a health Internet of things system. This unbreakable blockchain of personal medication history will provide means to avoid counterfeit products and to enable innovative logistic solutions.

Illicit fentanyls in the opioid street market: desired or imposed?

BACKGROUND: Illicitly manufactured fentanyl and its analogues are appearing in countries throughout the world, often disguised as heroin or counterfeit prescription pills, with resulting high overdose mortality. Possible explanations for this phenomenon include reduced costs and risks to heroin suppliers, heroin shortages, user preferences for a strong, fast-acting opioid and the emergence of Dark Web cryptomarkets. This paper addresses these potential causes and asks three questions: (1) can users identify fentanyl; (2) do users desire fentanyl; and (3) if users want fentanyl, can they express this demand in a way that influences the supply? ARGUMENT/ANALYSIS: Existing evidence, while limited, suggests that some users can identify fentanyl, although not reliably, and some desire it, but because fentanyl is frequently marketed deceptively as other drugs, users lack information and choice to express demand effectively. Even when aware of fentanyl's presence, drug users may lack fentanyl-free alternatives. Cryptomarkets, while difficult to quantify, appear to offer buyers greater information and competition than offline markets. However, access barriers and patterns of fentanyl-related health consequences make cryptomarkets unlikely sources of user influence on the fentanyl supply. Market condition data indicate heroin supply shocks and shortages prior to the introduction of fentanyl in the United States and parts of Europe, but the much lower production cost of fentanyl compared with heroin may be a more significant factor CONCLUSION: Current evidence points to a supply-led addition of fentanyl to the drug market in response to heroin supply shocks and shortages, changing prescription opioid availability and/or reduced costs and risks to suppliers. Current drug users in affected regions of the United States, Canada and Europe appear largely to lack both concrete knowledge of fentanyl's presence in the drugs they buy and access to fentanyl-free alternatives.

Global scenario of counterfeit antimalarials: A potential threat.

Malaria, a parasitic infectious disease causes approximately >1 million deaths annually worldwide. Treatment with effective antimalarials is one of the major strategies to combat malaria-related mortalities. However, there is a continuous threat of counterfeit antimalarials in the community. Counterfeit antimalarial drugs not only result in an economic loss but also decrease the efficacy of treatment resulting in the loss of faith in the health system and increases the the chances of drug resistance in the parasites. Counterfeit drugs hamper the intellectual property-based innovation paradigms as well. Awareness about these counterfeit drugs not only helps in avoiding drug resistance but may also enhance the drug therapeutic value. This review discusses the prevalence of counterfeit drugs in different geographic areas across the globe, the methods deployed for its detection and possible anticounterfeiting strategies. Literature search was conducted through PubMed, Google and International Pharmaceutical Abstracts using the terms 'counterfeit antimalarials', 'substandard', 'falsified', and 'drug resistance'. Free searches in other search engines included the terms 'antimalarial counterfeit drugs' and 'drug resistance'. Analysis of the literature survey indicated that majority of such studies were conducted in Southeast Asia and Africa region. The prevalence of substandard antimalarials was reported as high as 88.4% in Africa region and 53 % in Southeast Asia region. There is a need to follow a multifaceted approach to prevent the entry of falsified drugs with pre- and post-marketing surveillance. The samples need to be examined by regulatory bodies and strict legislation should be envisaged in order to maintain the quality of medicines.

The health consequences of falsified medicines- A study of the published literature.

OBJECTIVES: To analyse and present the literature describing the health consequences of falsified medicines, focusing on mortality and morbidity, as well as the scale of the issue, the geographic extent, the medicines affected, and the harm caused at both the individual and population levels. METHODS: We searched for articles in PubMed, using pre-optimized keywords '(counterfeit OR fake OR bogus OR falsified OR spurious) AND (medicine OR drug)'. Searches up to February 2017 yielded 2006 hits, of which 1791 were full-length articles in English. Among them, we found 81 papers that qualitatively or quantitatively described 48 incidents in which falsified medicines caused patients to suffer serious adverse effects, injury, symptoms or death. RESULTS: The distribution of incidents was examined according to the economic status of the countries involved, regional location in the world, therapeutic category of the medicines, number of incidents and victims by year, and characteristics of the falsified medicines. Among the 48 reported incidents, 27 (56.3%) occurred in developing countries and 21 (43.7%) in developed countries. These incidents involved a total of approximately 7200 casualties including 3604 deaths. CONCLUSIONS: Despite the poor quality of much of the reported data, the results of this study indicate that all types of medications have been targeted for falsification, and falsified medicines have had a serious impact on the health of both adults and children worldwide, with similar numbers of incidents in developing and developed countries.

Fentanyl: A Whole New World?

This article seeks to document the latest danger in the opioid crisis: fentanyl and related synthetic opioids. Fifty times more potent than pure heroin, cheaper to manufacture in laboratories worldwide, and easily distributed by mail and couriers, fentanyl is flooding the illicit opioid markets throughout the country.

Falsification of biotechnology drugs: current dangers and/or future disasters?

Falsified medical products have become a global threat since they were first mentioned to the general public at the conference of experts on the rational use of drugs organized by the world health organization (WHO) in 1985. Today, official estimates of the annual death toll due to falsified medical products range between two hundred thousand and one million. Although the extent of this global problem is the most significant in the developing world, an increasing number of reports have demonstrated the presence of a substantial (black) market for falsified medical products in the developed world. In recent years, also biotechnology drugs (synthetic peptide drugs and protein drugs) have been reported to be prone for falsifications. Next to the traditional doping related substances and image-enhancing polypeptides (e.g., human growth hormone, melanotan II) also essential medicines such as insulin, oxytocin and monoclonal antibodies have been falsified. The danger regarding the use of these falsified polypeptide drugs lies in the fact that end-users have no guarantee of the safety and efficacy of these preparations. Multiple reports have namely described the presence of the wrong active pharmaceutical ingredient (API), the wrong dosage or the absence of the API. Additionally, adverse health effects have been reported in the past due to toxic contaminations and product or process related impurities. Moreover, also unauthorized polypeptides or polypeptides which failed clinical trials or are still subject of clinical or pre-clinical assessments have been found in seizures of regulatory agencies. It stands to reason that regulatory agencies and analytical laboratories handling falsified biotechnology drugs have stepped up efforts to counter these grievous practices. The analysis of these falsified polypeptides and putative impurities is however not always straightforward. Often (bio)analytical laboratories have to resort to a combination of electrophoretic techniques, immunological assays and mass spectrometry based approaches to merely identify the content of seized samples. In addition, the difference in size (peptide vs proteins vs monoclonal antibodies), complexity (e.g., isoforms, glycosylations) and different synthesis techniques (chemical synthesis, recombinant expression, native protein isolation) result in a wide range of putative health risks. This review therefore aims to provide a brief overview of the genuine biotherapeutics present on the market and their quality prerequisites. Next, we describe the identification strategy utilised by our lab to identify the API in falsified biotherapeutics, followed by a discussion of the putative hazards due to impurities and contaminations that were found or could be encountered in falsified biotherapeutics. Finally, we terminate with an educational prediction of what may happen in the future and possible ways to counteract putative future disasters.

The Global Wicked Problem of Corruption and Its Risks for Access to HIV/AIDS Medicines.

We discuss how corruption affects access to antiretroviral therapies (ARVs) globally. Recent cases of theft of ARVs, collusion, and manipulation in procurement found in countries such as Central African Republic, Bangladesh, Malawi, and Guinea, show there is still much work to be done to reduce the risk of corruption. This includes addressing the structural weaknesses in procurement mechanisms and supply chain management systems of health commodities and medicines.