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The use of hydroxychloroquine, and to a lesser extent chloroquine, as a treatment against COVID-19 has received a lot of attention in the media. The news refers to very different aspects of its use, ranging from use within the situations authorized in the technical sheet and outside of them, as well as the development of clinical research with these drugs. The Spanish Agency for Medicines and Health Products (AEMPS) has prepared this document to clarify all these aspects and the position adopted on its use in clinical trials.
Use in authorized conditions
Chloroquine and hydroxychloroquine are active substances that have been authorized for a long time in different medicines. Initially they were used as a treatment for malaria and later they have found their greatest use in the context of different autoimmune diseases such as lupus or rheumatoid arthritis. They are, therefore, drugs with a well-known efficacy and safety profile.
It is very important to note that none of the published or ongoing studies have called into question the use of these drugs in the diseases for which they were already authorized and that patients taking these drugs can continue to do so by following the instructions they have received from the health professionals.
Use as a treatment for COVID-19 patients
With the onset of the pandemic caused by a completely new and unknown virus, and in the face of the health emergency situation, health professionals were making decisions according to the existing knowledge at all times, initially scarce and growing - although without reaching solid evidence - according to the days went by.
When there are no authorized drugs for a certain disease and while studies are being developed, one of the strategies is to use drugs that are licensed for other diseases and that could have a role in the treatment of the new disease (off-label use). The process of searching and eventual authorization of a new indication for a drug that is already authorized and that, moreover, may have been authorized for many years, is known as repositioning. This is what has happened with hydroxychloroquine and with many other drugs that have been used outside the authorized indications.
Precisely because hydroxychloroquine is a drug with some initial in vitro evidence, widely used, with a long history and with a well-known safety profile, in many countries healthcare professionals began to use it with COVID-19 patients.
In Spain, the AEMPS has coordinated, together with scientific societies, and the DGs of Public Health and Basic Portfolio, a document on the Treatments available subject to special access conditions for the management of respiratory infection by SARS-CoV-2 .This document provides information on the access conditions and the different treatments used are listed along with relevant information to serve as a guide for healthcare professionals. The document does not contain treatment recommendations and has always encouraged the development of the clinical investigations necessary to generate knowledge, warning of the potential risks of all, but, especially, of the simultaneous use of drugs that, such as hydroxychloroquine and azithromycin, can multiply its effects on the rhythm of the heart.
Even so, medical decisions for treatment are made with individual patients and within the protocols of each hospital center. Doctors make an individual assessment and based on that they prescribe the most appropriate treatments. In this context, and with the evidence available at all times, the centers have been varying their protocols and recommendations, the AEMPS has emphasized the need to take extreme precautions, to channel patients to clinical research settings, and to notify the suspected adverse reactions to the national pharmacovigilance system (see below).
Use in clinical research against COVID-19
As we have already commented, at the beginning of the pandemic, different in vitro study data suggested that hydroxychloroquine could be effective in limiting the replication of SARS-CoV-2 in addition to having an antiviral effect. This occurs with many in vitro drugs that later do not demonstrate any antiviral effect in real patients (hence the importance of not rushing to make assumptions before preliminary results with this or other drugs). In addition, there have been hypotheses that the potential effect of hydroxychloroquine in COVID-19 would not come from its antiviral properties but from its ability to interact with the immune system.
Thus, clinical research with hydroxychloroquine has evolved, on the one hand, by designing and launching clinical trials to assess its usefulness under controlled conditions and, on the other, by trying to collect data from extensive off-label use through registries or observational studies . Both types of studies are used to generate scientific knowledge and both have strengths and weaknesses. This aspect is important to understand the controversy generated.
To date, more than 200 clinical trials with hydroxychloroquine have been initiated around the world. Despite the high number of prospective, randomized, masked and controlled clinical trials, the evidence we have is still scarce and, at times, contradictory. The results of these studies will be communicated in the coming months and the AEMPS trusts that at least 20 of these trials will allow conclusions to be drawn, generate robust evidence about the efficacy of the treatment and guide possible recommendations for use.
Apart from clinical trials, a large number of observational studies have also been developed. These “hands-on” studies of treatment under real-world clinical practice are an extremely valuable supplemental source of evidence in many regulatory endeavors. However, by their very nature, they are subject to biases that are difficult to control and their results –although valuable and properly contextualized- do not in many cases generate scientific evidence as solid and incontrovertible as that generated by a clinical trial.
Although there had already been several publications of records, on May 22 the results of an observational study with a large volume of electronic medical record data from hospitals around the world were published. This investigation infers that the use of hydroxychloroquine and chloroquine isn't just not nonpartisan, but is associated with excess mortality in patients who take it. Although the study has generated a good number of criticisms, its publication triggered chain actions around the world by health professionals, promoters of clinical trials and regulatory agencies.
The first of all was the temporary suspension of the recruitment of a large clinical trial carried out in the United Kingdom (Recovery), which has already been restarted when it became clear that no safety problem had been detected in it that justified the suspension. The World Health Organization (WHO) temporarily suspended recruitment in the hydroxychloroquine arm of its SOLIDARITY trial, which studies the efficacy in terms of reducing mortality of 4 treatments against COVID-19, one of these treatments is hydroxychloroquine. WHO will make a decision on whether to continue the trial as soon as it completes an interim analysis of your data. Various European agencies have also spoken over the past week,
In
At this time, in
Aemps has published and regularly updates all clinical research information on COVID-19 , including licensed clinical trials and classified observational studies.
Suspected Adverse Reactions Related to the Use of Hydroxychloroquine in COVID-19 Patients
The AEMPS, together with the autonomous communities, and through the Spanish Pharmacovigilance System, regularly monitors and publishes data related to adverse suspicions reported with treatments used in COVID-19. The AEMPS has also published on April 22 (and updated on May 14) an informative note on precautions and surveillance of possible adverse reactions in patients with COVID-19.
Suspected adverse reactions due to hydroxychloroquine are those that were already identified and indicated in the technical specifications of the drugs. The data do not allow us to identify at this time an increased incidence of adverse reactions due to its use in patients infected with SARS-CoV-2.
Among the known adverse reactions are heart problems: Hydroxychloroquine can prolong the QT interval of the electrocardiogram, so healthcare professionals should be extremely vigilant when indicating treatment, especially if it is administered in combination with azithromycin - an antibiotic that is also arrhythmogenic. Some cases of neroupsychiatric disorders have also been identified. These adverse reactions are considered rare. Medical services experts have been encouraged to practice outrageous alert and cautiousness for the conceivable appearance of changes in conduct in patients treated with chloroquine or hydroxychloroquine for COVID-19,
Conclusions
The AEMPS will promptly monitor all the information that is produced, an intermediate safety analysis has been requested from the promoters of clinical trials, and in the absence of additional risks it will not adopt any other regulatory measure to suspend or temporarily paralyze the recruitment of patients in clinical trials to evaluate the efficacy of hydroxychloroquine. Patients who are now taking hydroxychloroquine inside or outside of clinical preliminaries for COVID-19 just as patients going through constant treatment with these medications should keep taking them and, regardless, keep up their typical subsequent meet-ups with their primary care physicians.
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