Substandard and Falsified Medications: A Barrier to Global Health Equity Exemplified in Ecuador

Abstract

Medicines have been developed and have become globalized at a pace faster than traditional medical education can keep up. Physicians, pharmacists, nurses, and advanced practice providers learn the names and functions of these medications, but not how they are made and how they get to the bedside. The often economically driven intricacies behind these processes have a dramatic effect on patient care and outcomes. A staggering proportion of medications worldwide are reported to be substandard or falsified. This article explores one country’s story of how medication gets to the bedside, describes how this process can go wrong, and outlines what providers can do to work toward the goal of equitable access to quality medications for all.

Introduction

One in ten medications in low-income and middle-income countries are substandard or falsified (SF). SF medications do not do what they are labeled to do or cause unexpected adverse effects. Substandard medications are ineffective or harmful due to poor manufacturing causing contamination or mislabeling or due to degradation of the active or inactive ingredients. Falsified medications are advertently mislabeled and may contain no active ingredients at all [1]. In 2017, it was estimated that only one third of National Medicines Regulatory Authorities (NMRAs), such as the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) in the European Union, had the capacity to conduct key regulatory functions that would prevent these SF medications from harming patients. Ecuador is an example of a country with ongoing reports of SF medications and is used here as a case study to shed light on the global burden of this problem.

A Primer on Regulation of Medication Safety

How has the supply of medications in the United States become so seamless that we rarely question their origin or integrity? In brief, the U.S. government and European authorities have played a large role in standardizing medications from the days of snake oil to the clinical trials of today. As early as the year 1000 BCE, there is documentation of the regulation of apothecaries. Ingredients and manufacturing processes, however, were not systematically scrutinized until the London Pharmacopoeia began publication in 1618 [2]. It took 200 years of subsequent editions to gain consensus among experts and exclude extraneously perilous ingredients [3]. The first American national pharmacopeia was published in 1820 in efforts to “rid the country of the evil and uncertainty in the preparation of medicine” [4]. Nevertheless, medication producers could say anything they wanted about their product regardless of the truth. It wasn’t until 1902 when the United States mandated labeling on food and drug products, and 4 years later legislation was passed outlawing misbranded or adulterated drugs. Despite this legal proclamation, the government was not equipped to evaluate claims and prosecute medication producers until more than 30 years later [5].

In 1938, more than 100 people died of poisoning from a sulfanilamide elixir containing diethylene glycol. New regulations mandated that the recently formed FDA must approve medications prior to them being allowed on the market. Approval was based on the review of ingredients and manufacturing practices but did not require evidence of efficacy and safety in humans. In 1961, thalidomide, marketed to treat morning sickness, was found to cause serious birth defects in children in Europe. In response to this, the FDA tightened its regulation and mandated that batch records and safety information be disclosed. The FDA started unannounced visits to production plants to enforce regulation and prohibited companies from manufacturing if they did not comply. The 1970s growth of biochemical technology and increased regulatory scrutiny contributed to a rise in medication prices. In an effort to decrease costs, new 1984 regulations allowed companies to produce bioequivalent medications after patent expiration of the branded product through an expedited FDA approval process [5]. Europe followed suit with similar policies driven by the EMA.

Pitfalls in Quality Control

Despite the pillar of accountability that the FDA became, the rate of drug discovery and quantity of companies that produce them have made it more difficult for the agency to prevent serious drug-related events. In 2012, a batch of Avastin® (bevacizumab) was found to have no active ingredient after 76 physicians had used it in hundreds of patients across the United States. There have been reports of patients finding glass and hair in their pills [6]. In 2013, 45 people died as a result of fungal meningitis linked to contaminated methylprednisolone injections compounded in Massachusetts [7].

The task of inspecting every drug manufacturing plant around the globe is labor-intensive and sometimes competes with economic interests. Oversight often becomes a game of catch-up, but the FDA and EMA’s reputation of rigor keeps the quality of medications in the United States and Europe relatively high, respectively [4]. In 1977, the World Health Organization (WHO) mandated the establishment of NMRAs in any country that wanted to import or produce medications [8]. Adoption of the mandate was slow at best, and as generic drug manufacturing and distribution grew so did reports of SF medicines. It was clear that direct enforcement of these regulations was needed, and in 2013 the WHO began to formally monitor drug quality through the Global Surveillance and Monitoring System for SF medical products [1, 2].

Ecuador as a Case Study

Regulation of medication safety in Ecuador has only recently taken shape and continues to evolve. Before the formation of a national public procurement service known as SERCOP in 2011, the government allotted money to each health center to buy medications, which led to inefficiencies and excess costs. Since then, SERCOP has centralized the process and now uses a reverse auction, through which pharmaceutical companies provide competitive pricing proposals and medications are then distributed by the government [9].

Applicants initially had to submit a chemical analysis of their product, but not proof of bioequivalence. Enrique Teran, a physician and pharmacology researcher in Quito, recounted that applicants could have scammed the system by submitting a brand name pill for analysis. Contracts were signed but subsequent inspections of selected manufacturing facilities found that many were not up to par and others were nonexistent. Some companies vanished while others were prosecuted [10]. For patients, there was a delay in medication access, a public uproar, and far more government expenditures than planned. Reputable international drug manufacturers moved to other South American countries with more welcoming economies as a result of mistrust and suspicion of corruption [11, 12]. In 2016, an amended auction process was repeated, in which SERCOP preemptively reviewed products in more detail [9]. Despite increased scrutiny, stockpiles of falsified medications were found in warehouses as recently as 2019 [13]. Ecuador’s equivalent to the FDA, the Agencia Nacional de Regulación, Control, y Vigilancia Sanitaria, works with law enforcement to crack down on such violations, but corruption and bribery have been blamed for ongoing transgressions [10, 11, 14].

Unfortunately, some of these low-quality medicines have gotten to patients before being intercepted. Dr. Nelson Maldonado, a neurointensivist in Quito, found many inconsistencies in the expected effects of medications compared with those he encountered during his training in the United States. Heparin did not lead to an appropriate elevation of activated partial thromboplastin time. Propofol and midazolam did not produce expected sedative effects in patients at up to three times the typical dose, and responses fluctuated by the vial. This led to difficulties treating status epilepticus and increased observed morbidity and mortality. Dr. Maldonado eventually left the public hospital because he felt he could no longer work in a system that did not have the infrastructure to allow him to properly treat his patients [15]. After further investigation and interviewing local health care providers, it was apparent that Dr. Maldonado was not the only one who noticed these inadequacies [15–17].

In April 2019, patients with chronic myelogenous leukemia noticed that when their medication nilotinib, a tyrosine kinase inhibitor, was switched from brand name Tasigna® to a local generic, they had more side effects, including dizziness, nausea, insomnia, muscle aches, and fatigue. An oncologist at a public hospital in Quito found that her patients who were provided generic nilotinib sustained remission for only 2 years compared with 5 years on Tasigna® [16]. Patients protested and in response, the contract with the generic manufacturer was terminated and patients were provided with Tasigna® [17].

Dr. Patricio Correa, a neuroimmunologist who trained in Spain, had ongoing challenges treating patients with multiple sclerosis (MS). In 2016, the government switched from brand name fingolimod (Gilenya®) to a generic called Lebrina®. Over the coming months, Dr. Correa noticed a pattern: patients who transitioned from Gilenya® to Lebrina® had increased hospitalizations and progression of disease. In 28 documented cases, there was a doubling in the Expanded Disability Status Scale from two to four and an increase in T2 fluid-attenuated inversion recovery lesions on magnetic resonance imaging from a total of 29 to 41 over the course of a year. In Correa’s cohort, 8% of patients on Gilenya® had been hospitalized compared with 22% of those who had switched to Lebrina® [18].

Maricruz Izurieta is one of approximately 270 patients in Ecuador with MS and was on Gilenya® [19, 20, 25]. She and a group of patients with MS went to court and to the media. Their outcry was that bioequivalence testing, as is normally conducted for generics before they go on the U.S. market, was never published for Lebrina® [21]. In Ecuador, this is not a unique phenomenon, and generic medications without bioequivalence testing are called “copy drugs” [21, 22]. Lebrina® had undergone some testing by a third party [23], but data on bioequivalence were not provided on request from the manufacturer. The courts decided that if patients show evidence of treatment failure with Lebrina®, they can be provided Gilenya®. However, as of January 2022, Gilenya® is still not available to patients in Quito [21, 24].

There are reports of poor-quality medications that do not make the news. Dr. Grace Salazar, a hematologist in Quito, noted that a formulation of oral hydroxyurea did not increase levels of fetal hemoglobin as it should in patients with sickle cell disease. She, along with other neurologists and a hospital pharmacist, reported that warfarin led to swings in international normalized ratio without changes in dose out of proportion to the norm [16]. This same pharmacist noted that patients taking oral furosemide did not have improvements in their fluid overload symptoms with increasing doses [26].

Neurologists at one of Quito’s public hospitals reported the Ecuadorian formulation of carbidopa/levodopa had a longer onset of action than another forms [27]. A generic of lamotrigine required higher doses, and generic carbamazepine was less efficacious and caused more side effects than their respective brand name equivalents. Dr. Daniella Di Cupua, an epileptologist trained in Spain, noted that she had found certain formulations of levetiracetam to be less effective than the brand name drug Keppra®. She reported good outcomes with an on-patent anticonvulsant drug lacosamide (Vimpat® made by GSK), but GSK left Ecuador because of difficulties in negotiating contracts with SERCOP [27].

Global Context

Ecuador is an example of a country whose NMRA is young compared with the United States and Europe. Most countries in the world are similar to Ecuador. Reports of SF medications hail from all over the world, but primarily Africa and Asia. Many of these are for SF antibiotics, antiseizure medications, and sedatives, which are commonly used in the critical care setting [28, 29]. Each of these classes of medications, when inadequately dosed or tampered with, can lead to adverse events. Uncontrolled seizures and infections can result in increased hospitalizations and mortality. Propofol is particularly dangerous because irregular fluctuations in effective dose can lead to hemodynamic instability [30]. Although the FDA’s reputation and scrutiny keeps many SF medications out the U.S. market, the consequence of such strict oversight are medication shortages. Critical care medications, particularly during the coronavirus disease 2019 pandemic, have been particularly taxed. Heparin had to be substituted with low molecular weight heparin in many institutions due to illness in pigs in China [31]. Normal saline was in low supply for months due to a hurricane in Puerto Rico [32]. The FDA publishes an online database of medications with shortages, which, at the time of writing this article, is about 100 medications long [33]. Medication shortages can occur due to national disasters and epidemics but are more often due to failed factory inspections or production company consolidation for economic reasons. Different sides of the same coin, medication shortages and SF products are reminders to not take access to medications for granted.

Global Response

Our team sent reports of discrepancies to the WHO Substandard and Falsified Medical Products working group. Anecdotal reports are just the start and need to be validated by chemical and functional equivalence testing. The Pan American Health Association (PAHO), a regional office of the WHO, works with member countries including Ecuador to intersect, report, and inform the public of incidents of SF medications [34]. In other parts of the world, the United Nations works with Interpol to criminally prosecute manufacturers and distributers who have knowingly participated in the spread of SF medications [35]. They also published a legislative guide to combating falsified medications for governments [36]. The World Bank and the International Council on Harmonization, made up of member pharmaceutical companies, work on a systems level to implement standards for medication regionally [37, 38]. Nongovernmental donor agencies, such as the U.S. Agency for International Development, The Global Fund, and The Bill and Melinda Gates Foundation, have funded efforts to vet the quality of certain medications for areas in need [38]. The U.S. Pharmacopeia is involved in at least two campaigns to promote quality in medications worldwide [39].

These efforts are a drop in the bucket compared with the work that needs to be done. For example, the UK identified 34,000 unregistered and unauthorized products advertised for sale as treatments for coronavirus just as recently as March 2020 [40]. PAHO found 596 reported instances of medications between 2017 and 2018 in Latin America. Their reporting mechanism is still new, and PAHO estimates that this is just a fraction of true cases, as evidenced by our experience in Ecuador [34]. SF medications continue to affect millions of patients. Some of these patients speak up, but most remain unaware that the medications that they take do not work. This results in more adverse effects, progression of disease despite perceived treatment, hospitalizations, and death. Quality medications that can save lives exist, and access to them depends on ongoing advocacy and systemic changes on the level of policy.

Conclusions

On the wall of the pharmacy waiting room inside of the public Hospital de Especialidades Eugenio Espejo in Quito, there is a poster entitled “Farmacovigilancia,” which translates to pharmacovigilance. It states that anyone can report adverse drug effects and therapeutic failures by filling out a “tarjeta amarilla”—a yellow card. Dr. Maldonado and many others at the hospital have filled these out time and time again. Despite the public hospital’s efforts, the yellow cards have yielded limited change. Many skilled providers have left for the private sector, in which patients self-pay for medications, because of this barrier to adequate patient care. Consequently, this leaves the most vulnerable population at the highest risk.

The plight for safe medications in Ecuador represents that of so many countries across the world and in our own communities. We all work diligently to prevent medication errors on an individual scale, but large-scale errors can fall through invisible cracks in the system. The timing of this issue is even more crucial while the world grapples with the aftershocks of a global pandemic, during which drug shortages in already overwhelmed critical care settings have had devastating consequences [41]. Although the FDA proactively collaborates with manufacturers to reduce the risk of critical drug shortages, many countries may not have the bandwidth to coordinate such an effort. These countries are not served by the large-scale trackable supply chains, leaving patients at an increased risk of obtaining SF medications, especially when supply chains are taxed during or after a pandemic [42, 43].

Luckily, a web of organizations has evolved since the turn of the century geared to address the very issue that physicians, pharmacists, and activists across the world have brought to light. Patients are speaking out and using local courts to get access to quality medications that work. They cannot succeed unless governments and industry step up to effectively serve their communities and customers.

Equitable access to quality medications globally requires a multidimensional approach. As health care providers, we have a responsibility to educate ourselves and a duty to advocate for not just individual patients, but for the safety of medical systems on a larger scale. The only things that separate us from the people of Ecuador are distance and the happenstance of history. Ecuador’s story could look more like ours were the FDA to become overwhelmed with a graver pandemic or more severe interruptions in the supply chain. More research is desperately needed to quantify the extent of SF medications around the globe, especially in Latin America. If you are interested in studying SF medications in your country or on an international level, please check out the resources in Table 1 and contact the authors to connect you to a network of experts who dedicate their lives to ensure that patients have access to safe and effective medications.

Table 1.

Resources for further reading and to get involved

Resource name	Link to resource
World Health Organization	https://www.who.int/teams/regulation-prequalification/incidents-and-SF/background
Bottle of Lies by Katherine Eban, 2019	https://www.harpercollins.com/products/bottle-of-lies-katherine-eban
Countering the Problem of Falsified and Substandard Drugs by The National Academy of Sciences, 2013	http://www.nap.edu/catalog.php?record_id=18272
International Conference on Harmonization	https://www.ich.org/
United States Pharmacopeia	https://www.usp.org/our-impact/medicines-we-can-trust#:~:text=Medicines%20We%20Can%20Trust%20is,and%20quality%20medicines%20for%20everyone%2C

Source of Support

No funding was associated with this article.

Disclaimer

The views expressed in this publication are those of the authors and do not necessarily reflect the official policy of the Department of Defense, Department of the Army, U.S. Army Medical Department, Defense Health Agency, or the U.S. Government.

Conflict of interest

The authors have no conflict of interest.