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The placebo problem

Leigh Frame, Ph.D., Master of Health Science, likes vitamin D. Executive director of the Office of Integrative Medicine and Health at George Washington School of Medicine and Health Sciences, she is especially interested in the role of vitamin D as an immune modulatory hormone.

She was starting a pilot study to determine the effectiveness of vitamin D supplementation via patch delivery (through the skin) versus pill delivery (via the gut) when the pandemic hit.

Vitamin D is a fat-soluble nutrient that also functions as a steroid hormone. Many of the body’s organs and tissues have receptors for vitamin D, which suggest important roles beyond what we currently know about its role in bone health.

Principles of research ethics

Respect for persons: Treat participants as autonomous; protect participants with decreased autonomy. Read more›››

Beneficence: First, do no harm; maximize benefits to participants; minimize risks to participants.

Justice: Fair recruitment of participants; participants asked to bear the risk should benefit from the research.

From “Ethical Concerns in Placebo-Controlled Supplementation Studies: How to Design a Rigorous Randomized Controlled Trial.” Permission from Leigh Frame.‹‹‹ Read less

“We had planned to bring 30 healthy subjects to the medical campus, who would otherwise not have needed to visit the campus,” Frame says. “Now, each visit would represent an added risk to them, which raises concerns in terms of the principles of beneficence and justice. Given that the benefit to these subjects is minimal as this study is not looking at potential therapeutic benefits, the risk of contracting COVID-19 through being on campus greatly outweighs the potential benefit to society. It would not have been ethical to proceed with this trial during the COVID-19 pandemic.”

 A SUDDEN HALT

The sudden emergence of COVID-19 meant clinical research was halted — or even terminated — in deference to the immediate needs of caring for patients and clinical trials focusing on the treatment and prevention of coronavirus infection were prioritized over studies focusing on other diseases. Once social distancing had been introduced by governments as a public health measure to prevent or slow the spread of disease, trial sponsors and investigators were required to determine whether ongoing trials should proceed. Several factors determined the fate of these trials, including trial location, the indication for the trial, the urgency of continuation, the safety of participants and staff, and risks to trial integrity.

The main question: Would it be ethical to continue?

“The field of research ethics has developed in response to research conducted without proper consideration for ethical issues or with blatant disregard for ethical concerns,” Frame wrote in a 2020 publication on ethical concerns in placebo-controlled supplementation studies. “The design of most research studies today involves more nuanced issues of research ethics relating to the Principles of Research Ethics.”

While Frame’s trial was put on hold, numerous studies were conducted on the potential of vitamin D to reduce risk of infection with COVID-19. Frame’s study looked at the efficacy of different supplementation methods: we already know that vitamin D supplementation can be beneficial, so investigating how this is best achieved fell short of the principle of beneficence. Using vitamin D as a preventative and potential adjunct treatment in COVID-19, however, was an unknown and potentially important in the fight against COVID-19.

“If you do a PubMed search for ‘vitamin D’ and ‘COVID,’ 936 results are returned from 2020 to 2021, plus 273 in 2022 as of June,” Frame says. “Those are substantial numbers, however if you restrict those results to clinical trials only, 30 results ranging from study protocols to completed results are returned from 2020 to Jun 2022. That is actually a very large number considering the extremely tight timeline from the emergence of COVID-19. Many of these studies, however, are observational in nature, meaning they are looking at vitamin D status in relation to COVID-19 infection and its progression and outcomes.”

ADDRESSING THE RISK

Observational studies are very low risk for the subjects, introducing very little additional risk to participants but offering potential benefit to society, though not the individual, Frame stresses. “Prioritizing this type of study during a pandemic makes sense ethically, not just due to the low risk, but because we have some evidence to inform a potential intervention that may prove beneficial. Vitamin D has known actions in viral infections and in the immune system more broadly. Therefore, it could be reasoned that vitamin D supplementation for prevention or as a potential adjunct therapy would be beneficial with minimal potential for harm.”

In these studies, the risk/benefit ratio is in favor of continuing. Keeping in mind the principles of beneficence and justice, it would be ethical to proceed.

“In fact, you could argue it would be unethical not to proceed,” Frame says. “Given the potential benefit to society, especially in a global pandemic, coupled with the potential benefit to the individual and the minimal risk they’d face. As this research would be done in those mostly likely to be affected by Covid-19, this bolsters the ethical nature of such studies. Plus, conducting research in those of greatest risk to morbidity and mortality from Covid-19 would further strengthen the justice component and could be used to improve health equity.”

Many of these studies found the same thing: insufficient blood levels of vitamin D were associated with increased risk of COVID-19 susceptibility, severity, and mortality.

Further research is still needed to determine the precise role and efficacy of vitamin D as a preventative or therapeutic measure in cases of COVID-19, but since vitamin D deficiency is common around the world, any link to its possibly helping surely justifies investigation.

Frame, and the principles of ethics in trial design, have concerns: One major concern with such studies is their use — or not — of placebo. Using a true placebo, an inert substance that participants believe is the therapeutic, has small positive effects in most cases, known as the placebo effect. However, this is likely smaller than an active control, in this case, a low dose vitamin D supplement.

Research is revealing that vitamin D has much broader effects than previously assumed, as it is an immune-modulating hormone. Vitamin D deficiency may lead to health issues involving infection, autoimmunity, cancer, chronic diseases such as cardiovascular disease, and even mental illness. Withholding vitamin D in clinical trials, therefore, may see harm done.

“As demonstrated in the Tuskegee Study of Untreated Syphilis, it is unethical to withhold treatment when there is a known, effective therapy,” Frame writes in Ethical Concerns in Placebo-Controlled Supplementation Studies. “This becomes less clear when talking about nutrition.”

COULD IT CAUSE HARM?

An individual may be found to have suboptimal or deficient stores of the nutrient in question. If they receive the therapy during the trial, their nutritional status should improve at least, even if the dose is insufficient to bring their levels to those required for the effect in question. If they are unfortunate enough to be placed in the control group, their nutritional status will not improve and may even worsen over the course of their treatment. This is the crux of the ethical issue, Frame says.

“Are we doing harm to these participants? That answer depends on many factors, but to be ethical we must maximize the benefits to participants and minimize the harm. I recommend using the current Recommended Dietary Allowance (RDA) as the active control in nutrition studies, which is the minimum amount most people need each day to avoid disease, but not to optimize health. A low dose of vitamin D would minimize risk, improving the risk/benefit ratio. However, this may make detecting differences between the groups more difficult by reducing the difference in effect sizes between the groups, requiring a larger sample size and increasing the cost of the study.”

As demonstrated in the Tuskegee Study of Untreated Syphilis, it is unethical to withhold treatment when there is a known, effective therapy.

– Leigh Frame

Above all, Frame advocates for weighing the risk/benefit ratio for each individual study during the study design process to optimize the potential for meaningful results from the study while protecting those participating:

“As a member of the research study team, it is your duty to protect your study participants and to ensure that your research is conducted ethically.”

Frame’s supplementation technique trial is still on hold. “We are hoping to start it very soon, as the risk of both contracting COVID-19 and the consequences of such infection have greatly decreased.”

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COVID was no barrier for UAE bird
enthusiasts

Research slowed during the pandemic for non-COVID matters as sputtering supply chains and closed labs made work difficult. But for a pair of amateur bird enthusiasts in the UAE, the skies were open and delivered an unexpected discovery.

The pair, then-chemistry teacher Oscar Campbell and physics teacher Simon Lloyd, made the outdoors their lab and discovered at an Abu Dhabi golf course a bird previously thought to be extinct and unknown in the UAE.

The steppe whimbrel is native to the Russian plains, remote areas of Kazakhstan and central Asia and is one of four whimbrel subspecies. It was declared extinct in 1994 and rediscovered in 1997, but its wintering grounds, in Mozambique, were not discovered until 2016. The UAE is a mid-way stop.

Campbell has been observing birds for many years, but spotting the juvenile steppe whimbrel was noteworthy.

We took hundreds of pictures. There are a bunch of features but the precise details of the underwing pattern are definitely the most diagnostic, critical ones

– Oscar Campbell

“It’s a significant finding,” Campbell says, because although there are an estimated 100 of them in existence, the fact that they found the young bird in the UAE means the species is continuing to breed.

Campbell and Lloyd had been doing monthly surveys of birds around the grounds of Saadiyat Beach Golf Club for about three years before they spotted the bird in August 2020. Campbell says the team at the golf club were excited about hosting such a rare bird.

Getting a look under the wing is crucial to identifying a steppe whimbrel. It was tricky, Campbell says.

“Part of the problem of course is most of the time you can’t see the underwings of a bird. And when you can see them, it’s flying so it’s moving fast. We took hundreds of pictures. There are a bunch of features but the precise details of the underwing pattern are definitely the most diagnostic, critical ones,” Campbell tells KUST Review.

The then-science teacher – now environmental scientist and ornithologist at Nautica Environmental Associates – regularly spent time out exploring and surveying birds as an amateur scientist for several other properties around the Emirates. He is currently working with a team on the third edition of Field Guide to Birds of the Middle East. The book is scheduled to be published in 2024.

Amateur scientists around the world are becoming more involved in research in a process growing in popularity known as citizen science. Amateurs work in collaboration with scientists to contribute data, analyze the data collaboratively or otherwise participate in projects.

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The bug named after a bug

The coronavirus left its mark on the world – and on a new species of insect found in the Western Balkans.

When Halil Ibrahimi and his team at the University of Prishtina discovered a new species of caddisfly – a flying insect similar to a moth whose eggs and larvae thrive in freshwater lakes, streams and ponds – they named it Potamophylax coronavirus.

The insect was discovered in Kosovo’s Bjeshket e Nemuna National Park before the pandemic, but the work of analyzing and describing it was done as the scientific world faced such challenges as lab lockdowns and difficulty accessing supplies.

The name is a good tool in increasing awareness for environmental protection.

– Halil Ibrahimi

This left Ibrahimi time to finish desktop research on previously started investigations. “Hence the name of the new species reflecting pandemia with all these obstacles,” Ibrahimi tells KUST Review.

But the name also has a second meaning.

It reflects “the hidden ‘pandemia,’ i.e. pollution and degradation of freshwater ecosystems in Kosovo and Western Balkans during the past two decades,” Ibrahimi says. “Many rare and important insect species, including the newly described Potamophylax coronavirus, are endangered by these activities.”

“The name is a good tool in increasing awareness for environmental protection,” he says.

Ibrahimi and the team published their results in Biodiversity Data Journal.

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Tech conceived during the pandemic
aims to calm a post-COVID world

A face mask developed during the pandemic to reduce stress and anxiety is evolving into a digital tool that can continue to serve its original purpose in a post-mask environment.

One of the winning teams of the 2022 Women to Impact venture of King Abdullah University of Science and Technology (KAUST) created a face mask called takeAbreath that monitors the wearer’s stress and anxiety levels. It then uses gaming technology to recommend breathing exercises to reduce any anxiety and stress identified.

The team – Anna-Maria Pappa, Sofia Dias and Leontios Hadjileontiadis of Khalifa University and Sahika Inal of KAUST – conceived the product during the height of the pandemic and are adapting the technology to offer relief for those who struggle with stress and anxiety.

Next generation
of face masks

People around the world wore masks in their daily lives during the pandemic to help prevent infection. Now, a new kind of mask might help diagnose illness. Read more›››

Engineers from MIT and Harvard say their new prototype can produce a COVID-19 test result in 90 minutes. The wearer breathes normally into the mask, and droplets produced by exhaling and coughing collect on a pad. The wearer then presses a button to activate the test. A small bit of water is released, flowing through the pad and rehydrating freeze-dried cells that react to the presence of coronavirus markers.After about 90 minutes, a colored line indicates whether the result is positive or negative. It looks like a pregnancy test. The team used a typical N95 mask and the results were published in Nature Biotechnology.This technology had been developed to detect other viruses such as Ebola. The MIT and Harvard teams have further plans for the technology. “We’ve demonstrated that we can freeze-dry a broad range of synthetic biology sensors to detect viral or bacterial nucleic acids, as well as toxic chemicals, including nerve toxins. We envision that this platform could enable next-generation wearable biosensors for first responders, health-care personnel and military personnel,” MIT researcher James Collins tells MIT news.Meanwhile, researchers at Khalifa University have been working on the NavaMASK, a sustainable and environmentally friendly mask made with a bio-based polymer that can be composted and integrated back into the ecosystem. “The NavaMASK not only addresses the pressing issue of mask waste but also highlights the importance of using renewable resources and minimizing environmental impact,” Shadi Hasan, director of KU’s Center for Membranes & Advanced Water Technology, tells KUST Review.‹‹‹ Read less

“In the end we do this to help people,” Pappa, who in 2019 was one of MIT Technology Review’s Innovators Under 35, tells KUST Review.

And now the team is adapting the technology into an app that, in its initial phase, begins with a simple breath into a phone and will eventually operate concurrently with wearable biosensors.

Users breathe into smartphone microphones, which capture the breath rate. The wearable biosensors read the wearers’ biological responses to stress. After the data is analyzed, the app recommends personalized breathing games to calm the heart rate and the wearer’s stress.

Breathing correctly, the team members say, is a skill people have to learn. They compare it to an athlete building endurance.

“Breathing in for seven seconds is not easy,” Dias says.

The team is working through some challenges around the many different brands of mobile devices and hopes to have a marketable product soon.

“Clearly, many development stages are on the horizon, yet we are hoping in one year to have the conceptualized idea transformed to a product. This will only happen with the intensive research efforts that we are currently undertaking, the support from Khalifa University and potential angel/venture funders,” Hadjileontiadis tells KUST Review.

The ultimate goal is for every breath to be a tool to “unlock our mindset toward stressless living,” Hadjileontiadis says.

According to the World Health Organization, stress and depression increased by 25 percent in the first year of the pandemic alone. It was so prevalent that it prompted 90 percent of countries surveyed to include mental health and psychosocial support in their COVID-19 response plans.

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Making this the last pandemic

There are a lot of people, Bill Gates included, who could have said “I told you so” at the start of the COVID-19 pandemic. In 2015, Gates warned a pandemic could happen and that the world was unprepared.

In How to Prevent the Next Pandemic, published seven years later, two years into a pandemic, Gates says, “Outbreaks are inevitable, but pandemics are optional.” At first glance, this seems optimistic, if not impossible: In a world this interconnected and interdependent, how can we reasonably and ethically contain outbreaks?

But the experts agree with Gates.

The World Health Organization’s Independent Panel for Pandemic Preparedness and Response says the COVID-19 pandemic was a sign of how vulnerable our world is:

“Our careful scrutiny of the evidence has revealed failures and gaps in international and national responses that must be corrected,” the panel writes in a 2021 report. “Current institutions, public and private, failed to protect people from a devastating pandemic. Without change, they will not prevent a future one. That is why the panel is recommending a fundamental transformation to a new system of complete pandemic preparedness. If we fail to take this goal seriously, we will condemn the world to successive catastrophes.”

Current institutions, public and private, failed to protect people from a devastating pandemic. Without change, they will not prevent a future one.

– WHO’s Independent Panel for Pandemic Preparedness and Response

“No one wants to live through this again ¬— and we don’t have to,” Gates writes. “If we make key investments that benefit everyone, COVID-19 could be the last pandemic ever.”

These key investments? Make and deliver better tools, including vaccines; improve disease monitoring; and strengthen health systems. Gates also advocates for a cross-disciplinary Global Epidemic Response and Mobilization (GERM) team that could contain outbreaks with speed and efficiency.

Some of these investments are already in the making: wastewater monitoring could keep an eye on infections in a community; mRNA vaccine technology has proved its efficacy; telehealth and health wearables changed the way we interact with health-care systems.

Others need more work. Gates calls for data to be available in real time, but data-protection laws and systems lag, and ethical concerns should not be ignored. Plus, changes need to be implemented worldwide, not just in countries that can afford it.

Gates’ calls for monitoring and responding to outbreaks are admirable, but a global coordinated effort is not realistic right now. Pandemics cross borders; they need countries to work together. They need collective investment and effective communication strategies. The COVID-19 pandemic proved some places are not ready, for socioeconomic and political reasons.

Dr. Eeshani Kandpal, senior economist in the Development Research Group of the World Bank, says pandemic-preparedness efforts should focus on the relationship between health inequity and broader social and economic vulnerability.

“The COVID-19 pandemic demonstrates that pandemic preparedness planning cannot be divorced from the fight against inequality,” Dr. Kandpal writes in a 2022 editorial for the British Medical Journal. “Addressing these dual challenges will require investment and political will. Gaps in countries’ capacity to finance health were large before the pandemic and have further widened in its wake, creating a fault line that threatens health security for all. Centering health equity in pandemic preparedness planning is not just the right thing to do, but also the smart thing.”