What Made Chloroquine and Hydroxychloroquine So Controversial During the COVID-19 pandemic?

By Sarah Paterson

Towards the end of 2019, a new coronavirus (COVID-19 or SARS-CoV-2) emerged in Wuhan, China. Little did we know the virus would spread worldwide, causing a major pandemic and putting our healthcare services under pressure. In 2020, the seriousness of COVID-19 became clear and the search for an effective drug therapy was on. Chloroquine and hydroxychloroquine were among those which were highly considered. With both drugs classed as ‘safe’ and ‘reliable’ (Touret and Lamballerie, 2020), in addition to their positive in vitro antiviral activity, their potential use in the treatment of SARS-CoV-2 was credible. However, shortly after clinical trials were initiated, both drugs’ benefits did not outweigh their known and potential risks and were revoked for emergency use. Although this was disappointing, clinical trials give pharmaceutical companies the opportunities to identify gaps in drug safety data, potentially leading to new and improved product labels/ leaflets, patient care and general knowledge surrounding active ingredients.

Talk in the media

Early in the pandemic, hydroxychloroquine and chloroquine received the strong focus of public attention of all potential therapies against SARS-CoV-2. As already licensed drugs, with well-established safety profiles, in vitro antiviral activity, and existing manufacturing processes, the potential for rapid distribution and at scale seemed promising. Therefore, interest for their clinical use in the treatment of COVID-19 escalated very quickly. While numerous clinical trials were initiated including the Solidarity Trial (an international clinical trial launched by the World Health Organisation and partners), discussions in the media had already surged. In the US, President Donald Trump gave multiple press briefings and made several comments on social media regarding the use of hydroxychloroquine and chloroquine. He referred to the drugs as ‘great malaria and powerful drugs’ and confirmed his own use of unapproved hydroxychloroquine to prevent coronavirus infection https://www. cnbc.com/2020/05/18/trump-says-he-takeshydroxychloroquine-to-prevent-coronavirus-infection. html. Trump unethically promoted the safety of the drugs stating ‘they have been around a long time, so they know the side effects’, ‘What do you have to lose. Take it’ thereby falsely advertising the products before clinical

trials were completed or considered safe for use causing an influx of sales and adverse events. Coronavirus and hydroxychloroquine: What do we know? - BBC News In addition, attention spurred on by the political leaders, such as Trump, French president Emmanuel Macron and Brazilian President Jair Bolsonaro - who expressed ‘there is no scientific evidence, but it has worked with me’ Coronavirus and hydroxychloroquine: What do we know? - BBC News - caused not only indiscriminate unsupervised use by members of the public but also created drug shortages and affected enrolment in clinical trials for other potential treatments.

The concerns

Both hydroxychloroquine and chloroquine have been used for more than 50 years for the treatment and prophylaxis of malaria, and more recently for autoimmune diseases such as Lupus and Rheumatoid Arthritis (Touret and Lamballerie, 2020). They are considered safe drugs with generally mild side-effects including: • Nausea • Vomiting • Diarrhoea • Abdominal discomfort.

However, the boundary between the approved therapeutic dose and toxic dose is very slim, therefore, if taken incorrectly, can be life-threatening. Chloroquine poisoning has been associated with severe cardiovascular disorders. More recently, COVID-19 clinical trial data, including a study published in the Lancet medical journal, has led to further concerns regarding cardiotoxicity and myopathy. The study presented an investigation into 96, 032 hospitalised COVID-19 patients from 671 hospitals worldwide. The authors established that patients treated with chloroquine or hydroxychloroquine were more likely to experience an abnormal heart rhythm and die in hospital than those who weren’t. As a result, in July 2020, the WHO suspended the hydroxychloroquine arm in the Solidarity Trial and the US Food and Drug Administration (FDA) revoked the products for emergency use (FDA Letter). https://www.who.int/emergencies/diseases/novelcoronavirus-2019/global-research-on-novel-coronavirus2019-ncov/solidarity-clinical-trial-for-covid-19-treatments The approval of a new product, or approval of a new indication of a product, needs constant pharmacovigilance monitoring to maintain and assess its overall benefitrisk profile. It is essential that new medicines should only be used as part of a clinical trial or in line with nationally agreed protocols. The encouragement given by the media and politicians was careless and led to important warnings given by authorities such as the FDA, European Medicines Association (EMA) and Medicine and Healthcare products Regulatory Agency (MHRA) advising against the use of these medications outside a hospital setting or clinical trial. https://www.fda.gov/drugs/ drug-safety-and-availability/fda-cautions-against-usehydroxychloroquine-or-chloroquine-covid-19-outsidehospital-setting-or

The silver lining

Pharmacovigilance is the science relating to the collection, detection, assessment, monitoring and prevention of adverse effects with all pharmaceutical products. Pharmacovigilance plays a critical role throughout a drug’s lifecycle - starting from clinical trials through to post-marketing. It is inappropriate to assume that a product is deemed ‘safe’ due to the number of years a product has been on the market. If a product is used outside of its approved indication(s), for example in an emergency like the COVID-19 pandemic, then it is highly likely that new safety data will be reported. In this case, both hydroxychloroquine and chloroquine were revoked for emergency use in COVID-19 patients due to new emerging clinical trial data. The process was fundamental in identifying necessary safety label updates, including undesirable effects such as anxiety and other psychiatric disorders and further information on the QTc prolongation, thus benefiting healthcare professionals and consumers. https://www.ema.europa.eu/en/news/ meeting-highlights-pharmacovigilance-risk-assessmentcommittee-prac-23-26-november-2020

Conclusion

It is unquestionable that the COVID-19 pandemic has been catastrophic in so many ways. It has been devastating for families, countries, economies and more. While the race to develop an effective vaccine seems to have been successful, the search for an effective drug treatment for COVID-19 and its complications remains an ongoing challenge. The healthcare industry will continue to collate and communicate safety information worldwide during its search for the next potential treatment, essentially keeping pharmacovigilance practices as a number one priority.

Sarah Patterson

Pharmacovigilance Associate Alliance Pharmaceuticals Limited