Unproven treatments in emergencies

During the COVID-19 pandemic, hundreds of interventions have been prescribed, promoted, and to varying degrees studied. Of these interventions, only a handful were ultimately proven to be effective and safe. Officials from the Pan American Health Organization (PAHO) therefore agreed during a webinar that emergency situations should not be an excuse to abandon the ethical and methodological precepts that govern clinical research and the use of drugs not tested under exceptional conditions.

“In practice, we have dealt with the feeling that certain rules work in normal times, and others apply in an emergency. The question is what are these other rules. What is not ethically acceptable, is that, in an emergency, anything goes. We have an obligation to conduct rigorous research,” said one of the speakers, Carla Sáenz, PhD, PAHO Regional Bioethics Advisor, in response to a matter of Medscape Medical News.

Sáenz added that rigorous research may be more difficult or may take a little longer, “but what takes longer is not doing research but continuing to give something, believing that later it will be shown that it works, and then it doesn’t,” she clarified.

Ludovic Reveiz, who is responsible for the knowledge translation program in PAHO’s Department of Evidence and Intelligence for Health Action, agreed. He holds a master’s degree in clinical epidemiology and a doctorate in public health. “Doing things right shortens time instead of lengthening it. When methodology is followed, results are achieved faster,” he said.

This does not appear to have been the most widely adopted approach in the early days of the pandemic, when hundreds of thousands or millions of patients were exposed to harmless and potentially dangerous drugs and other products. This has happened through low-quality clinical trials or discretionary off-label indications of drugs already approved for other conditions, as has been the case with ivermectin and hydroxychloroquine. Professional opinion or beliefs often guided treatment that went beyond the evidence.

For José Luis Castro, holder of a master’s degree in pharmacoepidemiology and international adviser to PAHO’s Medicines and Health Technologies Unit, the pressure generated by the emergence of health events or situations for which he there was no clear therapeutic approach is understandable. Added to this is the feeling conveyed by the media and social networks that doing something is better than doing nothing, “anything”.

“But doing things right takes less time than doing things wrong. We forget that these bad interventions have consequences. It is not without risk: we waste time and they can harm health,” said Castro, who also shared the results. of a pharmacovigilance study in five countries of the region (Colombia, Chile, Peru, El Salvador and Cuba) during the meeting. This study identified nearly 3,500 adverse effects to azithromycin, hydroxychloroquine, ivermectin, and other drugs used without evidence of efficacy against COVID-19 before August 31, 2020. Among these adverse effects , almost 12% (415) were classified as serious. The study is about to be published in the Pan American Journal of Public Health.

“It can’t happen anymore”

PAHO’s evidence summary on potential treatments for COVID-19 has been updated 37 times to date, and it critically appraises more than 200 interventions based on an analysis of approximately 700 clinical trials. , summarized one of its leaders, Reveiz. For most treatments, including those widely promoted, there is still uncertainty about the benefits and harms.

Some cause harm, although the level of certainty varies. Very few get the green light for certain benefits with moderate to high certainty: corticosteroids, oral antivirals and monoclonal antibodies. The appearance of new variants could affect their effectiveness.

“At the start of the pandemic, especially in the first year, a lot of interventions started being done without any evidence and based on very poor quality assumptions and observational studies. product because the interventions were there, because something had But in light of the current evidence, they had no positive impact on patients, they might have negative effects on some people, and in many cases we don’t even know because it hasn’t been measured,” says Reveiz.

Most of the interventions used turned out to be unnecessary or risky. In contrast, Reveiz noted that very few groups were administering corticosteroids until the positive results were published in June 2020. “Research is essential in these aspects,” he stressed.

Sáenz emphasized that in exceptional circumstances, unproven interventions can be used outside the context of clinical trials, always within a framework that provides adequate ethical and regulatory oversight, while generating evidence. This is what the World Health Organization has described as “monitored emergency use of an unregistered and experimental intervention” (MEURI), a framework developed after the 2014 Ebola outbreak that had not previously been adopted in the region.

Drugs and other unproven interventions “cannot be given, as they say, God’s way,” Sáenz stressed. According to the MEURI framework, four conditions must be met: (1) justification: a favorable benefit/risk profile has been established; (2) there is ethical and regulatory oversight; (3) there is a process to ensure informed consent; (4) the process generates evidence, that is, the use of the intervention is monitored and its results are documented and shared with the medical and scientific community in general.

For Sáenz, the COVID-19 pandemic has taught, among other lessons, that the MEURI framework must be applied in a “strictly” exceptional manner and that the collection of evidence can be delayed. One example has been the use of convalescent plasma, which in the United States has been given to 100,000 people under an expanded access program since late March 2020. “A clinical trial with less than a hundred times that number of participants showed that this intervention did not work. For this reason, randomized clinical trials should always be prioritized,” the official stressed.

She added: “During the pandemic, interventions were proposed as if they were within the framework of the MEURI, but without respecting the required ethical criteria. If they had been followed, I could have counted on the one hand on the treatments that were warranted. This cannot happen again in another health emergency.”

“Shortcuts are tempting and dangerous”

Pablo Richly, MD, director of the Center for Brain Health, in Quilmes Province, Buenos Aires, Argentina, has been an active social media advocate for the importance of evidence and a critic of unproven COVID-19 interventions . He often says his Twitter account during the pandemic can be compared to the famous Simpsons meme, Old Man Yells at Cloud – someone whose cries fall on deaf ears and experience misunderstanding or a rejection.

“A lesson from the pandemic could be that the popularity or spread of treatments was inversely proportional to the quality of evidence of effectiveness,” he said. tweetedfor example, August 25.

Speaking to Medscape, Richly recalled the phrase from an article in Science by bioethicists Alex John London, PhD, and Jonathan Kimmelman, PhD, as just over a month had passed since the declaration of the pandemic: “Crises are no excuse for lowering scientific standards. “

The authors were right, but they were ignored.

“The lesson should be that shortcuts are tempting and dangerous. Those who promote them are usually ignorant people or people with vested interests, which may be ideological, political or economic,” Richly explained.

Medscape asked him if, beyond “wrong” interests, many physicians might have acted on the inner belief that trying something, even without evidence, is better than taking a wait-and-see approach and if there was something in their professional training or their character. or social pressure that pushes them to action.

“It is clear that interests are not always conscious choices but can manifest through bias related to emotional factors. We are all vulnerable, so an open discussion based on public data is the best way to avoid that a lack of evidence only serves to reinforce prejudice.Ethics are key to science, but when the discussion devolves into a mere moralizing debate (e.g. saying that doing nothing is letting people die), it doesn’t. is more public health,” Richly replied.

Reveiz, Saenz and Castro are PAHO officials. Richly did not disclose any relevant financial relationship.

This article originally appeared on the Spanish edition of Medscape.

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