An Ethical Conundrum

Beyond the Curve: Dr. Peter Lurie's COVID-19 Blog

The thing about COVID-19 is that, for all the novelty of the virus and the innovativeness of the vaccines that will help us defeat it, the pandemic sometimes feels like an elaborate case of déjà vu—at least for those of us who’ve been sailing these public health waters for decades. Now an issue that kept me occupied for a good half a decade is back: the ethics of developing country clinical trials.

On its face, the issue is relatively simple. Thirteen vaccines have been authorized in at least one country—seven of these approved for full use—but the vast majority of the supply has been snapped up by developed countries. Some countries, trying to insure against vaccine failure or supply chain disruptions, have enough to vaccinate all adults more than once, while many countries—including most of Africa—languish with essentially no supply¹.

But how do we test the next generation of COVID-19 vaccines? Conducting a developed world placebo-controlled trial of the next vaccine, in which say half of the subjects are injected with saline instead of an active vaccine, seems unimaginable. But conducting the same trial in a developing country deprived of vaccine recently got a vote of support from a World Health Organization Ad Hoc Expert Group² which blithely concluded, “Countries with limited or no access to a known effective vaccine could thus ethically permit placebo-controlled trials of vaccines of potential relevance to them even if effective vaccines were already being marketed elsewhere.” No ethical justification was provided.

In 1997, my colleague Sidney Wolfe and I authored an article in the New England Journal of Medicine³ in which we argued that, given that the drug zidovudine had already been proved effective in preventing mother-to-infant transmission of HIV, future research, even in developing countries where zidovudine was not readily available, could no longer use placebos and should instead compare any future drug regimen to the regimen already proved effective.

This did not sit well with the research establishment and the controversy raged in the media, medical journals, and research conferences for years. Shortly thereafter, Wolfe and I unearthed another study—this one conducted by a pharmaceutical company developing a drug in a class called surfactants—in which some patients in developing countries with often-fatal Respiratory Distress Syndrome were to be randomized to placebos instead of one of the several surfactants that already had regulatory approval. Under pressure, the company abandoned the placebo group.

The proposal to conduct placebo-controlled trials of second generation COVID-19 vaccines raises similar ethical conundrums. In a special issue of the Indian Journal of Medical Ethics published today, I revisit the older, paradigmatic cases and compare those situations to COVID-19 vaccine trials. I demonstrate that the risks to placebo groups from not receiving a known effective vaccine are considerably smaller than the risks faced by the placebo groups in the zidovudine and surfactant trials. I also consider a range of alternative trials designs that might better protect trial subjects. Here’s what I conclude:

[T]urning to the developing world to conduct studies that would be unacceptable in developed countries simply on the ground that COVID-19 vaccines are generally unavailable in developing countries is not ethically justifiable. This is so whether the justification is rooted in total absence of vaccine in a given country or in developing country vaccine prioritization practices, because at root both derive from economic, not scientific conditions.

I do acknowledge in the article that the advent of viral variants may create genuine uncertainty as to whether existing vaccines are indeed effective (most were studied before the new variants were prevalent) and that this uncertainty could justify a placebo control, depending on vaccine characteristics, variant prevalence, the degree of variant resistance, and the acceptability of immune-bridging studies, which look at immune markers instead of clinical infection as measures of effectiveness. I conclude: “These factors must be considered together in the necessary case-by-case assessment of the ethical justification for any proposed trial.”

I invite you to consider my arguments in greater detail by reading the full article.

References

So AD, Woo J. Reserving coronavirus disease 2019 vaccines for global access: cross sectional analysis. BMJ 2020;371:m4750.
WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation. Placebo-Controlled Trials of Covid-19 Vaccines — Why We Still Need Them. New England Journal of Medicine 2021;384(2):e2. doi: 10.1056/NEJMp2033538.
Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. New England Journal of Medicine 1997;337:853-6.