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The True Cost of Vaccine Studies

In response to:

An Ethical Path to a Covid Vaccine from the July 2, 2020 issue

To the Editors:

Carl Elliott uses a review of Adverse Events: Race, Inequality, and the Testing of New Pharmaceuticals [NYR, July 2] by the medical anthropologist Jill Fisher to discuss a dilemma between two designs for efficacy studies of vaccines against the novel coronavirus.

Traditional designs to study vaccine efficacy are slow and can end without having reached statistically meaningful results. A challenge design may be substantially faster, or so the two of us (along with Peter Smith) have argued.* The main risks in a challenge study are greater per volunteer but can be brought down dramatically by recruiting only young, healthy volunteers. Either trial type risks accidents from the test vaccine’s toxicities or its enhancement of disease severity. In a traditional design, such accidents could happen to many more participants and take place in the field, not in the relative safety of a controlled medical environment. Challenge studies for a Covid-19 vaccine could help get us out of the current global pandemic faster, saving an incalculable number of lives and ending its disruptions of health care, food, and economic development, so they are worth considering.

While Elliott nowhere states his conclusion, he is clearly against challenge studies. That position is ill supported by his argument that there are both historical and present abuses in medical research. He traces a history of abusive Phase I trials, mainly for drugs, including nonconsensual trials that preyed on vulnerable prisoner populations before the current regulatory framework was introduced. He also points out some genuine problems in the current US system for medical research.

But how do these considerations even begin to answer which of the two efficacy trial designs now under consideration is preferable? To be sure, our article suggested that in these vaccine challenge trials, “multiple measures…be put in place to ensure that prior to consenting, potential participants fully comprehend the unusual risks involved in the study.”

It is true that challenge trials carry serious risks. But there are risks in either study type. Either can be done ethically or unethically.

Elliott insinuates that we neglected questions of payment to study participants. Our priority in the paper was to explain how to select participants with minimal likelihood of dying. Our dozens of later newspaper and TV interviews have repeatedly addressed questions of payment. While the matter is complex, our position resembles the one preferred by Elliott: payment for the risk taken would be a bad idea, although volunteers should be compensated for any accidents (which remain unlikely). They should be sustained and perhaps compensated for their long period in isolation but should not be lured by mammon to a risky trial. Again, though, why doesn’t Elliott direct the same critique at the traditional way of studying vaccine efficacy?

Nir Eyal
Henry Rutgers Professor of Bioethics
Rutgers University
New Brunswick, New Jersey

Marc Lipsitch
Professor of Epidemiology
Harvard T.H. Chan School of Public Health
Boston, Massachusetts

To the Editors:

In “An Ethical Path to a Covid Vaccine,” Carl Elliott discusses the growing call for “challenge studies” to test a potential vaccine against Covid-19. These would involve clinical trials of volunteers in which all of them receive the vaccine, but half are also deliberately injected with the virus. If the infection rate is no higher in this group, that would show that the vaccine is effective. The alternative is a typical and necessarily longer trial, in which the rates of naturally acquired coronavirus infections are compared in vaccinated and unvaccinated groups.

Elliott seems to think challenge studies would be acceptable, provided there are stringent protections and compensations for volunteers who might be harmed by being deliberately injected with a dangerous virus. Since he believes those necessary measures are extremely unlikely to be enacted, he is opposed. I admire Elliott greatly, so it’s difficult to argue with his thoughtful analysis, but I will. I don’t believe the door to challenge studies should be left even ajar.

There are two specific problems with even the most carefully done challenge studies of a Covid-19 vaccine. First, we still know very little about this novel virus, including what hidden or longterm effects it might have on even young, healthy volunteers. And second, will a vaccine be equally effective in the elderly and chronically ill, those who are most vulnerable to Covid-19? Elliott acknowledges this problem, but I think it may be more serious than he implies.

But more generally, I worry about the erosion of our hard-won ethical consensus (starting with the Nuremberg Code) that people should not be used as means to an end if they might be harmed. There is also a risk of bribery or coercion in enrolling volunteers, even if they are officially unpaid. I believe this erosion of our ethical standards, even for a good cause, would be a very unfortunate precedent. We would then be on the proverbial slippery slope downhill.

Marcia Angell, M.D.
Former Editor-in-Chief
New England Journal of Medicine
Santa Fe, New Mexico

Carl Elliott replies:

Nir Eyal and Marc Lipsitch suggest that my aim was to discuss a dilemma between two designs for vaccine efficacy studies. In fact, my aim was to make sure that potential volunteers for Covid-19 vaccine challenge studies were aware of some critical issues that advocates have failed to mention. First, if research subjects in the United States are sickened or injured in a trial, they may well face financial ruin on top of their illness. Most sponsors require subjects to pay for their own medical care, and virtually none guarantees compensation for pain, suffering, or the inability to work. Second, many of the current industry sponsors of vaccine trials have a record of burying, spinning, and rigging their research. (The list of such sponsors includes Merck, for which Lipsitch consults.) Third, even if a trial leads to a vaccine, we have been given no guarantees that it will be made available to those who can’t afford it, raising the possibility that the sacrifices made in vaccine trials will yield benefits primarily to the rich and well insured.

None of these problems is unique to challenge studies. What is unique about those studies is the extraordinary number of people willing to volunteer without being told about the fine print. This is a recipe for exploitation. Eyal and Lipsitch claim their priority in their article was “to explain how to select participants with minimal likelihood of dying,” yet in the study design they proposed, some subjects up to the age of forty-five would be exposed to the coronavirus after getting only a placebo vaccine.

Like Marcia Angell, I’m disturbed by the use of subjects as a means to an end, especially when the risks are unknown. If I left the door to Covid-19 vaccine challenge studies ajar, I can think of no one better than Angell to close it. In fact, we may need to close a lot more doors. In Phase I trials, researchers routinely use subjects as a means to an end, even when the risks are significant and the subjects are vulnerable. That slope was slippery and we have reached the bottom. We need to find a way back up.

  1. *

    “Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure,” The Journal of Infectious Diseases, Vol. 221, No. 11 (June 1, 2020).