Rush to risky challenge trials is unethical
The people and financial resources invested in developing a vaccine against the novel coronavirus that causes COVID-19 are staggering; the results to date unprecedented. The first human clinical trials started in March. Six months later, there are 44 vaccines in clinical trials and more than twice as many in non-human pre-clinical trials.
Of the 44 vaccines in human clinical trials, 11 are in Phase III randomized controlled trials. These trials involve tens of thousands of healthy volunteers, some of whom are immunized with the candidate vaccine and some of whom receive a placebo. All go about their daily lives with the instructions to take appropriate public health precautions to avoid contracting the virus. As people encounter the virus, researchers learn whether those who were vaccinated were protected from infection. Typically, this process takes a few years to complete but efficacy data could be available in less time if the trials are conducted in places with high rates of infection. Meanwhile, since March 2020, some including Dr. Anthony Fauci, the Director of the National Institute of Allergy and Infectious Diseases in the U.S., have been promising a vaccine within 12 to 18 months.
Those committed to compressing the timeline argue the conventional pathway that relies on natural infection is too slow. They advocate the use of human challenge trials that involve considerably fewer research participants, perhaps just a few hundred. The healthy volunteers would be housed (isolated) in a biocontainment facility – a state-of-the-art research facility with immediate access to healthcare should this be needed. They would be given a candidate vaccine and then, a month or so later, would be deliberately infected with a purified, attenuated strain of the coronavirus at a dose that would cause mild disease. They would then be monitored to see if they become infected.
For obvious reasons, this proposal is controversial. Clinical researchers are not in the habit of asking healthy volunteers to assume serious risks (including death) when there are no effective therapies to offer should the volunteers become infected. The antiviral drug remdesivir has shown some modest benefit in treating patients with severe COVID-19 symptoms but is not effective in those with mild symptoms. Further, there is growing evidence that severe infection can have long-lasting neurological and cardiovascular effects and decrease overall lung function. And yet, infectious disease specialists and Members of Parliament have advocated the use of human challenge trials for coronavirus vaccines.
According to the Financial Times, researchers at Imperial College London plan to move forward with a challenge trial involving healthy young adults who are thought to be at lower risk. We don’t yet know which vaccines they intend to test, where the clinical trial will take place and whether and how much research participants will be paid. We do know that there are multiple regulatory hurdles, including review and approval by the U.K. Medicines and Healthcare Products Regulatory Agency and that appropriate research ethics committee review will be required.
The Financial Times has speculated that the remuneration for participation in this trial would be higher than £3,750 (approximately $6,500 Canadian) that is the current remuneration rate for influenza challenge studies. The payment would likely be higher because the isolation period after infection probably would be longer and the risk to participants greater.
The issue of fair compensation highlights one of the many ethical challenges with challenge trials – the twin risks of exploitation and coercion. Is “$6,500+” too little or too much for those consenting to a small chance of death or serious disability? Many find themselves in a depressed economic state as a direct consequence of the pandemic. Some are jobless and cash strapped. The Canadian government has provided financial support through the Canada Emergency Response Benefit program. For many Canadians, these funds have been essential in helping to keep a roof over their heads and food on their tables.
Now the question becomes whether an offer of $6,500+ for a month’s work as a research participant would be a coercive offer – an offer that would be difficult (if not impossible) to refuse because of personal circumstances and limited options.
On the other hand, is $6,500+ too paltry a sum to offer someone to assume the small risk of death for the benefit of developing a safe and effective vaccine? Is this a fair exchange or an exploitative offer, where a vulnerable person is being asked to assume too much risk for too little reward? Exploitation involves taking advantage of another’s vulnerability. In Canada, or similarly wealthy nations, this might mean taking advantage of a person who has perhaps long been economically disadvantaged and is now destitute. On a global scale, it might mean taking advantage of people in low- and middle-income countries with limited resources.
Even if it were possible to successfully reduce the harms of coercion and exploitation, the risk of harm with challenge trials is unwarranted given that it is not the only way to speed up vaccine development and secure the hoped-for-benefit of reducing the number of lives lost to COVID-19. Further, depending on how the challenge trial is designed, it might not speed things up at all. There are other trial designs with a more favourable harm-benefit ratio.
Thousands of researchers across the globe have redesigned traditional clinical trials to create adaptive trial designs that shrink the traditional timeline. Adaptive trial designs allow significant flexibility where traditionally designed trials do not. For example, adaptive designs can allow for seamless Phase I/II clinical trials (to test both safety and efficacy at the same time), explore multiple vaccines simultaneously, drop or add candidate vaccines or adjust participant enrollment numbers. All of this can be done using state-of-the-art statistical tools that ensure modifications do not undermine a trial’s integrity or validity and ultimately allows for much faster and potentially less expensive clinical trials. For example, the Adaptive COVID-19 Treatment Trial (ACTT) provided evidence for the modest efficacy of remdesivir.
We support the laudable goal of working faster to produce safe and effective vaccines against this novel coronavirus. However, moving forward with a challenge trial at this time, when it seems clear that this goal can be achieved using adaptive trial designs, is unethical.