Biotechnological therapies and biosimilars for COVID-19: scarcities, poor regulation, and pharmaceutical black market: a case analysis in Ecuador

Generics and Biosimilars Initiative Journal (GaBI Journal). 2021;10(4):184-92
DOI: 10.5639/gabij.2021.1004.023

Published in: Volume 10 / Year 2021 / Issue 4
Category: Review Article
Page: 184-92
Visits: 1050 total, 7 today
Keywords: biosimilars, black market, COVID-19, interleukins, tocilizumab

Author byline as per print journal:
Esteban Ortiz-Prado1, MD, MSc, MPH, PhD(c); Enrique Teran2, MD, PhD; Raul Patricio Fernandez Naranjo1, MSc; Doménica Cevallos-Robalino1, MD; Eduardo Vasconez1, MD; Alex Lister3, MPH

Abstract:
At the beginning of the COVID-19 pandemic, Ecuador was unprepared for the overwhelming number of COVID-19 cases. As the general population started to see the effects of the pandemic, unproven treatments and medications were sought by the population to try to ameliorate the impact of the pandemic.
The growing demand for a cure, the fear of dying from COVID-19, and the lack of therapeutic rigour, pushed a significant number of people to seek help outside the traditional healthcare system. Doctors, pharmacists, and patients started prescribing or self-medicating pharmacological products that were later shown to be ineffective, toxic or even contraindicated. In Ecuador, most people who developed the severe acute respiratory syndrome associated with infection by the coronavirus 2 (SARS-CoV-2) virus, which causes COVID-19, used antibiotics (azithromycin), antiparasitic medications (hydroxychloroquine or ivermectin), dangerous chemical products (chlorine dioxide) and in some cases, biological medicines, to try to cure or protect themselves from COVID-19.
The growing demand for therapies that were unavailable, as well as the rise in misinformation, created the perfect scenario for the misuse of medicines and enabled the appearance of a rampant black market of unregistered biological products. In this manuscript, we describe the Ecuadorian experience in relation to the off -label use of biological and biosimilar products during the COVID-19 pandemic, the role of the pharmaceutical black market, and the lack of national regulations to avoid dangerous practices.
To the best of our knowledge this is the first report that has aimed to describe the unapproved and even illegal sale and use of biologicals, biosimilars and related products, with or without approved therapeutic indications in the treatment of COVID-19.

Submitted: 17 August 2021; Revised: 9 November 2021; Accepted: 11 November 2021; Published online first: 24 November 2021

Introduction

The COVID-19 pandemic has sparked a race for pharmaceutical companies to focus on developing new drugs and vaccines to deal with the disease. It has also led to the reuse of marketed drugs approved for other clinical indications to treat patients suffering from COVID-19 [1]. Biologicals, biotechnology drugs, or bio-pharmaceutical products are large complex biomolecules with a heterogeneous structure, they are extremely sensitive to process changes and generated by cells or living organisms through recombinant deoxyribonucleic acid (DNA) technology, controlled gene expression, or antibody production. They encompass a wide range of substances, including hormones, vaccines, growth factors, blood products, monoclonal antibodies, and advanced technology products, e.g. protein–antibody combinations and gene therapy biological products [2]. Biosimilars have been defined as ‘a copy version of an already authorized biological medicinal product with demonstrated similarity in physicochemical characteristics, efficacy, and safety, based on a comprehensive comparability exercise’ [3]. Unlike small molecule generics, biologicals are larger and more complex, and therefore production can be difficult to standardize; even within the same manufacturing facility, it is not possible to produce a copy biological in the precise manner that a small molecule can be replicated.. Thus the term ‘generic biologic’ is inappropriate [4].

Since the beginning of the pandemic, several biotechnology companies joined the race to find effective medical treatments for COVID-19 and there are now more than a thousand clinical trials either completed or ongoing to evaluate their utility [5]. However, most of these studies have used or are using the original biological molecule, largely due to the lack of available biosimilars.

At the beginning of the pandemic, Ecuador suffered an extensive crisis in terms of excess deaths per capita, and there were no therapeutic options available other than chloroquine and hydroxychloroquine [6, 7]. While the first clinical trials were being conducted elsewhere, in Ecuador, for political reasons, fear, or ignorance, public authorities, some doctors, and the community per se, began to use and self-prescribe medicines [8] that were not supported by evidence that they could either reduce mortality or increase the chances of survival [9, 10].

In addition, in Ecuador, as in the vast majority of Latin American and developing countries, the availability of originator biotechnological products is limited, and once available, their accessibility is quite limited, particularly in public health institutions [11]. For these reasons, there is a growing interest in biosimilars as an alternative, not only for price reduction, but also for market improvement [12]. In addition, due to the lack of biosimilars or the scarcity of original molecules, smuggling from other countries or even the counterfeiting of these medicines can create a black market for pharmaceuticals [12].

Methods

Study design and setting
This is a descriptive analysis of the mechanisms and efficacy of existing biotechnological products approved for use in other diseases but now being used for COVID-19, as well as those developed specifically to treat COVID-19. In addition, this report offers an overview of the availability of biosimilar products and can be classified as an “expert literature review”, according to Grant’s classification [13]. Finally, a summary of the events that occurred in Ecuador is presented as a case analysis of the effects of poor pharmaceutical product regulation and a pharmaceutical black market.

Data sources and search strategy
Information from primary and secondary sources was obtained from research databases. The databases included PubMed / Medline, ScienceDirect, search engines such as Google Scholar and Google. Indexed manuscripts were retrieved using the Boolean operators AND/OR in combination with the words ‘biosimilar’, ‘biosimilares’ (Spanish), ‘biological drugs’ or ‘medicamentos biologicos’ (Spanish). This search combined the term ‘COVID 19 or SARS-Cov2’ using the truncation mark (*) to include all documents containing the specified word at the beginning of the search with the word ‘market’ in English and Spanish.

Results

Antitumour necrosis factor-alpha (TNF)-α agents
TNF-α is an essential mediator of the acute and chronic systemic inflammatory response, leading to the production of other cytokines and chemokines. Therefore, anti-TNF-α therapy has been widely used in inflammatory arthritis. Infliximab is a chimeric monoclonal antibody indicated for inflammatory conditions, including rheumatoid arthritis and inflammatory bowel disease. In the UK, the CATALYST randomized trial is currently investigating the use of infliximab in managing the inflammation of patients hospitalized with clinical features of COVID-19. Some investigators consider that anti-TNF-α agents could be useful in COVID-19 [14, 15] However, there is very little evidence to support the use of anti-TNF-α therapy in this type of patient, particularly with infliximab [16]. CT-P13, an infliximab biosimilar, manufactured by the South Korean biotechnology company Celltrion, which in partnership with the University of Oxford and Birmingham University Hospitals, is investigating it as a treatment for COVID-19 symptoms in the phase II CATALYST trial [17, 18]. If a benefit of CT-P13 therapy is demonstrated, this is likely to lead to further exploration through larger-scale trials (RECOVERY or REMAP-CAP) [19].

Anti-IL-1 therapy
All available studies detected high levels of pro-inflammatory cytokine IL-1, particularly IL-1β, in the serum of COVID-19 patients [20]. Anakinra is a recombinant human IL-1 receptor antagonist that has shown to benefit patients with autoimmune diseases associated with macrophage activation syndromes [21]. It also has had limited use in severe COVID-19 patients and in some cases was considered as second-line therapy in these patients [22]. Based on this, the testing of other anti-IL-1 molecules like canakinumab, and rilonacept, has been undertaken, but confirmation of their efficacy for COVID-19 treatment requires further studies in randomized controlled trials. Although there are several biosimilar candidates for anakinra, none have been authorized yet, either by the US Food and Drug Administration (FDA) nor the European Medicines Agency (EMA), and therefor there is no evidence for their efficacy in the treatment of COVID-19.

Interferon-beta-1a therapy
In viral infections, the immune responses that restrict the transfection of healthy cells by the virus are the link to the production of cytokines, particularly type I interferons (IFN) [23]. Among these, interferon-beta (IFN-β) is best known for its antiviral activities [24]. Due to the previously reported efficacy of IFN-β in SARS-CoV-2 [25] and its mechanism of action, different clinical trials using IFN-β were conducted worldwide. Based on the evidence reported in these, a series of clinical trials with ReciGen (interferon beta-1a, CinnaGen), a biosimilar, were designed and conducted in multiple centres in Iran [26]. One study reported lower hospitalization time, improved prognosis, and lower mortality rate for patients treated with interferon beta-1a. However, this study had several limitations, including a small sample size, lack of a control group, and testing ReciGen only in conjunction with other medications. Investigators reported that the reason they did not use a control group was because they had ethical concerns about depriving patients of potentially effective treatments. Additionally, investigators were unable to observe the effects of ReciGen alone because all patients received hydroxychloroquine and lopinavir/ritonavir in accordance with the national Iranian guideline on COVID-19 treatment [26].

Anti-IL6 therapy
Tocilizumab (TCZ) is a humanized monoclonal antibody of the IgG1 subclass. It inhibits the binding of cytokine, interleukin 6 (IL-6) to its receptors and, therefore, reduces this cytokines’ pro-inflammatory activity by competing for soluble and bound forms. Chugai Pharmaceutical Co. Ltd was initially in charge of developing this drug in collaboration with researchers from Osaka University, but by December 2001, F. Hoffmann-La Roche AG, commonly known as Roche, a Swiss pharmaceutical company obtained the opt-out rights to TCZ in the US. After this, Roche signed an agreement with Chugai to jointly develop and promote TCZ in all countries except Japan, South Korea, and Taiwan [27, 28]. Roche fi led marketing applications with FDA and EMA in late 2007 [27]. TCZ’s primary use is treating rheumatoid arthritis, systemic juvenile idiopathic arthritis, and polyarticular juvenile idiopathic arthritis [29]. The primary considerations when using TCZ are its immunosuppressive effects, which increase the risk of infection, and its negative influence on the lipid profile [29].

TCZ effectiveness in the treatment of patients with COVID-19 is still under analysis. Initial trials carried out in China, Switzerland, Italy, Qatar, and France suggest that TCZ is effective in producing rapid relief of respiratory symptoms; decreases in inflammatory markers; improvement in the level of oxygen saturation; and improved overall condition of patients, and reduced mortality [30-32]. While other studies support the use of TCZ to reduce admission to intensive care units (ICUs) and mortality rate; however, its use did not prevent clinical aggravation or mechanical ventilation [33-35].

Overall, the patient criteria for the proper use of TCZ in subjects with COVID-19 include: [a] extensive and bilateral lung disease in seriously ill patients with elevated levels of IL-6; [b] a high level of D-dimer and/or C-reactive protein (CRP) and/or ferritin and/or fibrinogen in a progressive increase; and [c] worsening of respiratory exchanges that require invasive or non-invasive ventilation support [36].

Sarilumab is another fully human monoclonal antibody that inhibits binding to IL-6 receptors that was developed to treat rheumatoid arthritis [37]. It has reportedly shown a higher affinity for binding with IL-6 receptors, which translated into higher receptor occupancy and greater reduction in CRP levels compared to TCZ [38]. Sarilumab has also been shown to reduce the time that critically ill patients spent in intensive care by about a week [39].

Finally, siltuximab, a human–murine chimeric monoclonal antibody, is indicated for the treatment of adult patients with multicentric Castleman’s disease, a rare lymphoproliferative disorder driven by dysregulated production of IL-6 [40]. In a small study of patients with moderate COVID-19, the 30-day mortality hazard risk was significantly lower after the use of siltuximab [41].

Although there are several TCZ biosimilar candidates, none have yet been approved by FDA or EMA. To date, there are also no biosimilar candidates for the other IL-6 inhibitor biologicals.

Janus kinase (JAK) inhibitors
Inflammatory cytokines, such as IL-6 and TNF, bind to the cell surface receptors, then tyrosine kinases, such as Janus kinase (JAK), bind to the intracellular portion of these receptors. Once these cytokines bind to each receptor, phosphorylation of transcription factor signal transducers and activators of transcription (STAT) are induced along with JAK phosphorylation. Then, the phosphorylated STAT (STAT-1/2/3/4/5A/5B/6) form a dimer and migrate into the nucleus to control gene transcription with consequent T-cell activation and cytokine release from immune cells, including IL-2, IL-6, IL-7, IL-12, IL-15, IL-21, IL-22, IL-23, and IFN-γ [42].

The JAK family consists of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Different JAK inhibitors target one or more of these JAK members, and they can theoretically inhibit multiple cytokines simultaneously. To date, three anti-JAK drugs have been marketed: tofacitinib, inhibiting JAK1, JAK2, and JAK3, as well as baricitinib and ruxolitinib; both acting against JAK1 and JAK2 [43].

Baricitinib has the added ability to prevent the invasion of viruses into lung cells and immediately inhibits JAK activity induced by cytokine stimulation. Therefore, baricitinib could theoretically prevent both the invasion of viruses into the lung cells of patients infected with SARS-CoV-2 and the pathogenic induction of cytokine storms. On the other hand, tofacitinib, another JAK inhibitor, does not prevent viruses from entering the cells [44].

There are few studies of baricitinib as a COVID-19 treatment and those that exist are of it combined with lopinavir/ritonavir. All of these have reported earlier hospital discharges and reduced death rates. However, the only study with ruxolitinib did not demonstrate any significant changes in time to clinical improvement, mortality rate, or virus clearance [45].

Nucleotide analogue therapy
Remdesivir inhibits RNA synthesis, by competing with native adenosine triphosphate for chain inclusion, and as a result, it delays chain termination [46]. Remdesivir (GS-5734) was developed by Gilead Sciences and emerged from a collaboration between Gilead, the Centers for Disease Control and Prevention (CDC), and the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) [47], to treat Ebola [48]. Remdesivir has also showed to be active against filoviruses, paramyxoviruses, pneumoviruses, and coronaviruses [49].

Remdesivir proved to be a potent inhibitor of SARS- CoV-2 replication [50] in the epithelial cells of the human bronchial airway and nose. FDA approved remdesivir in severely hospitalized COVID-19 patients on 1 May 2020 [51]. In October 2020, this drug was the first to be approved for the treatment of COVID-19 for all paediatric and adult patients, irrespective of the severity of the disease [52].

The ‘Adaptive COVID-19 Treatment Trial’ (ACTT-1) study showed that remdesivir was associated with faster recovery (31%) compared to placebo. The results also suggested a survival benefit, with a difference in the mortality rate of 3.6% from those who received the drug vs those who received the placebo [52]. The effectiveness of remdesivir was linked to in-hospital treatment of 5 days infusion with the drug. However, some studies revealed that not all patients had this length of hospital stay [53].

More recently, data published from the ACTT-2 study (NCT04401579) reported that treatment with barcitinib plus remdesivir was superior to remdesivir alone in patients with COVID-19 pneumonia receiving high flow oxygen or non-invasive ventilation. The combination therapy reduced recovery time and showed improvement in clinical status [54].

Barcitinib was part of the international collaboration known as the World Health Organization’s Solidarity trial. The trial enrolled 11,330 patients from 30 countries and reported that remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had no benefit in overall mortality, initiation of ventilation, and duration of hospital stay in patients with COVID-19 [55].

Remdesivir has been approved for emergency use in severely ill patients in India, and South Korea. The drug is also currently approved in the US and Japan for the treatment of moderate to severe COVID-19 [56, 57]. However, in July 2020, Gilead Sciences announced that until November 2020, all remdesivir produced had been sold to the US and would not be available to other nations [58]. The company signed an agreement with the government of India that allowed remdesivir to be produced in India by seven Indian companies. In April 2021, the government of India stopped the exportation of the drug due to the increase in domestic COVID-19 cases [59].

Anti-CD6 therapy
Itolizumab is another monoclonal antibody. By inhibiting CD6, it downregulates the synthesis of pro-inflammatory cytokines and adhesion molecules. This eventually leads to reduced levels of interferon-γ, interleukin 6, and TNF-α [60]. On 11 July 2020, the pharmaceutical company Biocon, received approval from India’s general drug controller to commercialize an itolizumab injectable solution for the emergency treatment of hospitalized patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19 [18]. This approval was based on evidence that many itolizumab treated patients made a full recovery and were discharged from hospital. However, the scientific community has observed inconsistencies and possible fallacies related to the design of the study. In addition, the study cannot be considered randomized due to the withdrawal of two patients who experienced adverse events that were excluded from the analysis of the trial. One of these patients later died [60].

Therapy against SARS-CoV-2 based on monoclonal antibodies
The SARS-CoV-2 genome encodes four major structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N), as well as non-structural and accessory proteins [61]. The S protein is further divided into two subunits, S1 and S2, that mediate host cell attachment and invasion. Through its receptor-binding domain (RBD), S1 attaches to angiotensin-converting enzyme 2 (ACE2) on the host cell. This initiates a conformational change in S2, resulting in virus-host cell membrane fusion and viral entry [62].

Neutralizing antibodies to SARS-CoV-2 in unvaccinated patients infected with COVID-19 are produced about 10 days after disease onset, with higher antibody levels observed in those with severe disease [63]. The neutralizing activity of COVID-19 patients’ plasma was correlated with the magnitude of antibody responses to SARS-CoV-2 S and N proteins [64]. However, each patient exhibits a unique bio-distribution pattern of SARS-CoV-2 neutralizing antibodies, making the development of anti-SARS-CoV- 2 antibodies a real challenge [65]. Despite this, it was proposed that monoclonal antibodies targeting the S protein might have the potential to prevent SARS-CoV-2 infection, to alleviate symptoms, and limit progression to severe disease in patients with mild to moderate COVID-19, particularly in those who have not yet developed an endogenous antibody response [61].

Many neutralizing SARS-CoV-2 antibodies are in the development and preclinical investigation stages, with most focusing on the spike protein and thereby preventing viral entry into the host cell. Several of these SARS-CoV-2 antibody candidates are undergoing clinical trials, and three of them, LY-CoV555 (Eli Lilly/AbCellera), REGN-COV2 (Regeneron), and CTP59 (Celltrion), have recently received emergency use authorization. Other antibodies against SARS-CoV-2 in various stages of development include: JS016 (Eli Lilly/Junshi Biosciences, phase I), TY027 (Tychan, phase I), BRII-196, and BRII-198 (Brii Bio/TSB Therapeutics/Tsinghua University/the 3rd People’s Hospital of Shenzhen), and SCTA01 (Sinocelltech Ltd/Chinese Academy of Sciences) [66].

Ly-CoV555 (bamlanivimab), is an antibody therapeutic that acts against the spike protein of SARS-CoV-2 that was developed jointly by AbCellera and the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID/ NIH) in the US. It is a recombinant IgG1 neutralizing monoclonal antibody that binds to the receptor-binding domain of the spike protein of SARS-CoV-2. It can inhibit the binding of the virus to the human angiotensin-converting enzyme-2 receptor, and prevent the virus from entering the cell [67]. This was the world`s first SARS-CoV-2 specific antibody to enter a clinical trial for the prevention and treatment of COVID-19 (in early June 2020). In November 2020, the co-producer, Lilly, was granted emergency use authorization for LY-CoV555 by FDA [68].

It has been shown that, following SARS-CoV-2 inoculation, prophylactic therapy with LY-CoV555 resulted in substantial reductions in viral load (gRNA) and viral replication (sgRNA) in the lower respiratory tract. Furthermore, on days 2 to 6, subjects who received LY-CoV555 had slightly less severe symptoms than those who received a placebo [67]. The drug LY-CoV555 is currently being used in clinical trials for the treatment and prevention of COVID-19 (NCT04411628; NCT04427501; NCT04497987; NCT04501978).

On 21 November 2020, FDA also approved the mixture of (IgG1κ) and imdevimab (IgG1λ), an antibody cocktail developed by Regeneron Pharmaceuticals Inc that had been shown to reduce hospitalization rate in high-risk patients with mild-to-moderate infection with SARS-CoV-2 [69]. IgG1κ and IgG1λ are two recombinant human monoclonal antibodies that have unmodified Fc regions and bind to non-overlapping epitopes of the spike protein receptor-binding domain (RBD) of SARS-CoV-2 [70]. A study examining IgG1κ and IgG1λ potency in preventing infection with the UK, South Africa, and Brazil variants of SARS-CoV-2, concluded that this cocktail is most efficient in patients who are exposed to the wild-type SARS-CoV-2 rather than the new variants [71].

South Korea’s Celltrion Healthcare has developed CT-P59 (regdanvimab), a human monoclonal antibody that blocks interaction regions of SARS-CoV-2 RBD for angiotensin-converting enzyme 2 (ACE2) receptor with an orientation that differs from previously described RBD targeting monoclonal antibodies. This monoclonal antibody lowers the risk of COVID-19-related hospitalization and oxygenation; specifically, it lowered the rate of progression to serious COVID-19 in patients aged 50 and older. The mean time to recovery was 3.39 days across all CT-P59 treatment groups compared with 5.25 days among patients who had received placebo, but this difference did not reach statistical significance [72, 73].

Etesevimab (also known as JS016, LY3832479, or LY-CoV016) is a recombinant fully human monoclonal neutralizing antibody. It specifically binds to the SARS-CoV-2 surface spike protein receptor-binding domain with high affinity and can effectively block the binding of the virus to the ACE2 host cell surface receptor. Point mutations were introduced into the native human IgG1 antibody to mitigate effector function. Lilly licensed LY-CoV016 from Junshi Biosciences after it was jointly developed by Junshi Biosciences and the Institute of Microbiology, Chinese Academy of Science (IMCAS). Junshi Biosciences leads development in Greater China, while Lilly leads development in the rest of the world [74]. According to FDA, when compared to a placebo, bamlanivimab has been shown to decrease COVID-19-related hospital admissions or emergency department visits in patients at high risk of disease worsening in the 28 days following therapy. However, the results of a study by Robert et al. reported no substantial change in viral load reduction when bamlanivimab monotherapy was used, but that the cocktail of bamlanivimab plus etesevimab could be effectively used in combination for the treatment of COVID-19 [75], presumably because bamlanivimab and etesevimab bind to separate yet overlapping epitopes in the RBD region of the S protein. Combined use of these two neutralizing monoclonal antibodies has been demonstrated to accelerate the decline in viral load at Day 11 and reduce treatment-emergent resistant variants [76].

Biotechnological drugs during COVID-19 pandemic in Ecuador, a case study
Early media reports reported that the COVID-19 related cytokine storm could be controlled by the inhibition of IL-6 through treatment with TCZ. They also suggested that the antiviral remdesivir, might be useful to help combat the disease. After publication of these reports, and prior to any regulatory approval or access, people sought to obtain these drugs out of desperation, fearing their relatives could die outside or inside hospitals [77, 78].

Tocilizumab use and its black market
Roche introduced TCZ into the private market in Ecuador in 2009, where it was authorized for treatment of rheumatoid arthritis. It was not included in the National Formulary to be used by public institutions until 2019. This was an important milestone for the drug’s purchase by public institutions; a system that is primarily based on a drug’s approved formulary indication.

On 27 March 2020, on the advice of 28 national experts, who were mainly physicians and infectious disease specialists, the Ecuador Ministry of Health, issued a guideline of treatment for patients with COVID-19. This included TCZ as an alternative treatment for cases of severe pneumonia that were not responsive to other drugs [79]. This decision was based on the early results of COVACTA (NCT04320615), a phase III, randomized, double-blind, placebo-controlled, multicentre study to evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of TCZ in combination with the standard care given to hospitalized patients with severe COVID-19 pneumonia [80]. However, this guideline appears not to have considered that, for the drug to be used in public institutions, a waiver of the original indication would be necessary to allow physicians to prescribe it.

This guideline was later reviewed and revised several times, and although some contradictory data was published on the efficacy of TCZ in the treatment of COVID-19 patients, e.g. CORIMUNOTOCI [81], REMDACTA [82], EMPACTA [83], and MARIPOSA [84] trials, it remained a recommended drug for second- or third-line treatment in COVID-19 patients with severe pneumonia.

During April and May 2020, the numbers of COVID-19 cases were rapidly increasing in Ecuador, particularly in the large highly populated city of Guayaquil on the Pacific Coast. Simultaneously, a growing number of physicians in the private sector were reporting good patient outcomes following TCZ treatment. There was however no approved protocol or methodology to monitor or report results. This led to a temporary, nationwide sellout of TCZ. In response, Roche Ecuador donated units of TCZ to the public sector in an apparent attempt to facilitate access.

At this point, the availability of TCZ was communicated through social media networks. It was evident that there was a black market for this medication, the source of which focused on Mr Abraham Muñoz, a weight trainer from Guayaquil. Mr Muñoz was reportedly a close friend of a well-known provider of medical supplies, Mr Daniel Salcedo, and his brother, Mr Noe Salcedo.

This led to reports of a chain of corruption within public hospitals that was set up to resell TCZ vials that had been purchased by or donated to the hospital. The regular price per vial was US$340 but subsequently, vials were available on the black market for US$1,200 [12]. It was also reported that the medicines had not been stored in cardboard boxes at the required 2–8 degrees Celsius [85]. Due to this, it is likely that the medicines were ineffective at time of their administration [86, 87]. Abraham Muñoz and Noe Salcedo were convicted of the theft and illicit sale of TCZ. Their prison sentences were eight and seven years, respectively [88]. Daniel Salcedo was also linked to other corruption cases related to sales of medical consumables at inflated prices during the pandemic and for which he was sentenced to 13 years in prison [89].

February to April 2021, saw another rise of COVID-19 cases, largely focused on the capital of Quito. This led to further TCZ shortages and illegal sales at inflated prices of as much as US$1,000 per vial [90, 91]. The National Authority alerted the population about this illicit action but they did not implement any action to control it [92]. In addition, Roche Ecuador explicitly communicated that the sole operator authorized to deliver vials to public and private institutions and highly specialized pharmacies was Quifatex SA [93]. Data from the biggest of these specialized pharmacies (January–May 2021) revealed that TCZ was requested for 389 patients, mainly from the highlands (68%) and predominantly those aged between 51 to 70 years old (52%). The average request per patient was for four 200 mg TCZ vials. It is important to note that, of these patients, 53% were from the public sector, even though the Ministry of Public Health did not alter the national formulary to allow physicians in the public sector to prescribe TCZ for treatment of COVID-19. Finally, in an unpublished follow-up of 133 of those patients, 60% confirmed that they had recovered from COVID-19 (personal communication with F Puente & C Mendia).

Remdesivir was not registered in Ecuador until September 2021; therefore, it was not available nor authorized for medical use in the country prior to this date [94]. The Ecuador Ministry of Health treatment guidelines, published on 25 November 2020, recommended against the use of remdesivir in patients with SARS-CoV-2 infection [95]. However, on 26 July 2020, the Vice-Minister of Health publicly announced, through the Embassy of Ecuador in Washington DC, that Ecuador had requested a total of 20,000 doses of remdesivir from Gilead Sciences [96]. On 4 August 2020, 1,900 doses of remdesivir were delivered to Ecuador for the treatment of 320 intensive care patients in public hospitals in Ecuador, with many in the capital Quito [97]. There was confusion over whether the doses were a donation or purchased by the government of Ecuador for US$70,000 [98]. The use of remdesivir, as a “compassionate drug” was then ruled out by an official document from the Ministry of Health issued on 13 August 2020 [99]. In addition, the fact that it was unclear how the doses were to be distributed and used generated controversy in the country [100].

The February to April 2021 period of high numbers of COVID- 19 cases led to illegal commercialization of remdesivir in Ecuador through social networks [101], as had also been seen with TCZ. Despite the product not being available in Ecuador, this period saw a rise in prescriptions for remdesivir by physicians nationwide. This is thought to be as the result of suppliers issuing fake assurances and health certificates to sell this product. At that time, prices for a vial of treatment with this drug ranged from US$250 to US$850 [102].

Based on a visual inspection of some vials, the “source” of the product was either the US or India. Vials are likely to have arrived in Ecuador via courier delivery using a sanitary emergency waiver provided by the health authority [103]. However, it was not possible to determine whether the inspected vials, requested for “emergency use” belonged to a real patient. In addition, it appeared that in many cases, the product was requested by the same physician and for relatives from the same family. This seems to be at least one source of the product sold on the black market in Ecuador (Personal communication with Ing. Gallardo, former Sanitary Control, Regulation and Surveillance Agency (ARCSA) Director).

The fear of getting infected with SARS-CoV-2 and the lack of availability of appropriate treatment drugs led to the inappropriate use of drugs in Ecuador. This also led to the Internet commercialization of the drug products noted previously, as well as other drugs such as aspirin, dexamethasone, and ivermectin [104]. As a result of these facts, the Ecuador Ministry of Health’s ARCSA has been monitoring social networks since July 2020. In the first year of monitoring they found 270 cases of illegal sales [105].

The main limitation of this report is the lack of published information. Much of the information mentioned was taken from newspapers or other news reports. Unfortunately, there is a lack of reliable, official or regulatory data on these issues. One goal of this report is to encourage collection and publication of such data in Ecuador, as well as other countries.

Conclusions

The COVID-19 pandemic has acted as a driver for more rapid development, evaluation, and publication of biotechnological drug use. However, there remains a scarcity of information on both the approved and unapproved use of biosimilars and their availability in resource poor countries for the treatment of COVID-19.

In Ecuador, legal frameworks exist for the approval, commercialization, and use of pharmaceutical products, including biosimilars. However, although in the vast majority of health institutions there are pharmacy and therapeutic committees, unfortunately there are no specific mechanisms in place to avoid and prevent their misuse or even overuse. The commercialization of pharmaceutical products by individuals is a criminal offense, and to prevent this, the national health authority must identify those responsible, prosecute them and mark a precedent. More importantly, the illegal use of pharmaceutical products, particularly those requiring special conditions like cold storage, represents a serious public health concern.

Funding sources

This work: design of the study and collection, analysis, interpretation of data, and writing, did not receive financial support of any kind except for the publication fee paid in full by Universidad de las Americas, Quito, Ecuador.

Authors’ contributions

EOP and ET were fully responsible for the conceptualization, data collection and elaboration of the study. RFN, DCR and EV contributed to the elaboration of the literature review. AL critically reviewed the entire manuscript and produced several comments prior to the submission.

Acknowledgements

Data about tocilizumab were kindly provided by Cristina Mendia and Fausto Puente from Welkom Medicamentos de Especialidad (www.welkom.com.ec).

Competing interests: None.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Esteban Ortiz-Prado1, MD, MSc, MPH, PhD(c)
Enrique Teran2, MD, PhD
Raul Patricio Fernandez Naranjo1, MSc
Doménica Cevallos-Robalino1, MD
Eduardo Vasconez1, MD
Alex Lister3, MPH

1OneHealth Research Group, Universidad de las Americas, Ecuador Calle de los Colimes y Avenida De Los Granados, Quito 170137, Ecuador
2Colegio de Ciencias de la Salud, Universidad San Francisco de Quito, Quito 170901, Ecuador
3University of Southampton, University Road, Highfield, Southampton SO17 1BJ, UK

References pending to upload

Author for correspondence: Esteban Ortiz-Prado, MD, MSc, MPH, PhD(c), Director del Grupo de Investigación, OneHealth Research Group, Universidad de las Américas – Ecuador, Calle de los Colimes y Avenida De Los Granados, Quito, 170137, Ecuador

Disclosure of Conflict of Interest Statement is available upon request.

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