Clinical trials: ethics, quality and urgency are being reconciled in the current pandemic?

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A race against the clock began to find solutions to stop the Covid-19 pandemic. But this is no reason to abandon the scientific rigor of clinical trials.

It is thanks to rigorous clinical trials that the development of vaccines against epidemic diseases, so often reported when epidemics are not in the news, has resulted notably in the eradication of smallpox and the near - elimination of polio worldwide. In addition to the successes achieved in the field of vaccination, antiviral therapeutic research has also had major victories to its credit, for example, with the development of antiretrovirals that control HIV or treatments that now cure hepatitis C.

In recent decades, the general public has discovered that certain infectious agents, known only to scientists outside of epidemic periods, can spread and kill. These emerging or reemerging viruses pose new challenges for medical research. Faced with the emergency, and under pressure from the political power, which is transmitting the media and social pressure, the scientific community must adapt its standards and practices. But how far?

What methodologies for reliable clinical trials?

Today, clinical trial methodology is essentially based on the performance of "randomized controlled" clinical trials. These allow the comparison of groups of patients receiving different treatments, in parallel.

In a randomized controlled clinical trial, a first group of patients is defined as the "experimental" group. It is made up of patients who receive the treatment to be evaluated, whose safety and efficacy must be studied. When multiple drugs are studied at the same time, there may be more than one experimental group.

The second group is defined as the "control" group. These are patients who receive the standard treatment if there is one, that is, a treatment with proven efficacy in the pathology of interest or a placebo, if there is no standard treatment. This group allows to reflect the evolution of the pathology when the experimental treatment is not administered.

When performing a test without a control group, therefore, it is difficult to determine the actual effect of the treatment. In fact, if the patients' condition improves, we cannot know if the reason is that the treatment is effective or if it is because, even in the absence of treatment, their condition would still have improved. The latter case means that the treatment does not change the natural course of the disease and is therefore ineffective.

Finally, the term "randomized" means that the allocation of the treatment to be administered is decided, for each patient, by means of a draw that makes this choice unpredictable. This randomization allows homogeneous and balanced groups of patients to be obtained who, therefore, have the same probabilities of improvement, cure, worsening or death. Due to this initial balance, if a difference (in safety of use or effectiveness) is highlighted at the end of the test, it can be attributed to the difference in treatment.

A context of health emergency.

Recent epidemics of Ebola virus disease in West and Central Africa show how medical and scientific actors have been able to adapt to reconcile the imperatives of quality of care, public health, and ethical medical research in emergencies.

With more than 28,000 cases and 11,300 deaths in a few months in West Africa, this epidemic that lasted from December 2013 to the end of 2015, the deadliest to date, was a race against time for all actors.

The emergency was first and foremost a public health and humanitarian emergency, with the aim of quickly detecting, isolating, and treating infected people. But the magnitude of the epidemic has made it possible and essential to test new vaccines and treatments identified in animals in humans, during the preclinical phases, or already used in humans for other viral infections. These new molecules could be evaluated in record time in phase I and II clinical trials (study of the effectiveness of the new drug, its dosage and pharmacodynamics). Some therapeutic studies were randomized, others not, because their sponsors believed that the treatments studied offered a better hope of survival (which subsequent statistical analyzes generally did not show).

A respected ethical framework

In terms of ethics, the research protocols were subject to double approval, that of the ethics committees of the promoting countries, especially in Europe and North America, and that of the ethics committees of the countries where the research was carried out. research, mainly Guinea, Liberia and Sierra Leone.

Innovative procedures must be implemented to obtain the free and informed consent of patients in situations of extreme tension and vulnerability, isolated in Ebola treatment centers with personnel with full protective equipment. The original written consents were unable to leave the contaminated area for filing, due to significant infectious risk, they were photographed from a distance. In the absence of loved ones in bed, the health care teams were responsible for their informed choice, in complete independence of the investigation teams.

These advances allowed the first randomized phase II-III study to be carried out during the recent Ebola epidemic in the Democratic Republic of the Congo (2018-2020), with several treatment arms (group of participants who received the same treatment or the same absence of treatment, according to the protocol), during which two treatments rigorously demonstrated their effectiveness.

Reconciling ethics, quality and urgency is not impossible in times of crisis.

The experience of Ebola virus disease outbreaks shows that research that combines ethics and quality can be done under extreme conditions, which test health systems and social codes.

Therefore, despite the virtual absence of health systems in the countries affected by these epidemics and the massive collapse of the social fabric of the affected populations, who were no longer able to approach the living or honor their dead, the knowledge of The disease and identification of However, treatment has progressed. These results were possible thanks to the work of international research teams that involved local staff: mediators (called "Champions" by the researchers of the "PreVac" vaccine project - Association for Research on Ebola vaccination), research technicians , researchers, health workers, etc.

Faced with these challenges, research carried out in an epidemic situation requires ethical reflection, in order to guarantee compliance with ethical norms, taking into account cultural specificities, health systems and norms in terms of medical care at the local level. , as well as the complexity of the research conditions and the vulnerability of the participants.

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