Placebo vs. access to the available vaccine
Few modern clinical research trials have been followed by the public as closely as the current COVID-19 vaccine studies. It should be no surprise that nationwide media reports have focused on and debated the trials’ protocols and informed consent processes.
On Dec. 2, a World Health Organization (WHO) ad hoc expert group published an editorial in the New England Journal of Medicine about why placebo-controlled trials of COVID-19 vaccines are still needed — even as the vaccine is rolled out to the public.1 “While vaccine supplies are limited, available vaccines are still investigational, or public health recommendations to use those vaccines have not been made, we believe it is ethically appropriate to continue blinded follow-up of placebo recipients in existing trials and to randomly assign new participants to vaccine or placebo,” the group wrote. “Moreover, under these conditions, we believe that trial sponsors are not ethically obligated to unblind treatment assignments for participants who desire to obtain a different investigational vaccine.”
The last statement started an ethics debate on the social media platform Twitter, in which the question of how ethical this approach is, unless it is spelled out clearly in the informed consent. Several people who said they were participants in a COVID-19 trial chimed in and said they had not been informed of this. To note, the language in their informed consents was not provided.
“This opportunity to obtain reliable evidence about longer-term effects would be destroyed by early unblinding and immediate vaccination of participants assigned to placebo,” the WHO ad hoc group wrote. “Although each participant has the option to pursue any available intervention, if substantial numbers of participants choose not to do so, continuation of blinded follow-up in a population in which no licensed vaccine is being deployed could yield important and unexpected findings that would be difficult to obtain reliably any other way.”
On Dec. 2, The New York Times (NYT) quoted a married couple in a vaccine study who thought they would receive the vaccine as soon as it was shown to be safe and effective.2 The wife said she received a modified consent in November that indicated people in the placebo arm of the trial may have to wait up to two years to receive the vaccine, “if they get one at all.” The woman told the NYT that she was “owed” that vaccine.
Ethics During a Pandemic
Pfizer issued a statement in October that it would vaccinate the placebo arm of its trial. “If Pfizer’s vaccine is granted emergency use authorization, we would propose to amend our ongoing study to allow crossover of eligible placebo subjects to the active vaccine arm if they wish to do so at any time. The statistical considerations and details regarding the appropriate protocol language, informed consent, and logistics of this process would need to be carefully developed together with the regulatory authority.”3
“There are always potential ethical issues and spillover effects when you are talking about conducting clinical trials on vaccines in the middle of a pandemic,” says Tim K. Mackey, MAS, PhD, associate professor at the University of California San Diego, and Director of Healthcare Research and Policy at UCSD - Extension. “First among them is the fact that study participants who are not receiving the intervention (in the control arm) may drop out of the trial when a vaccine begins to become available to the public, either through another vaccine candidate approval or based on a shorter study, etc.” This could lead to dropout as participants do not know if they are in the control or treatment arm, he says. In addition, participants who have consented still may choose the security of knowing if they were vaccinated.
“I also think that it is possible that a study participant could try to procure access to a vaccine (such as another candidate that has been approved) while in a study,” Mackey says. “Then, they would typically not meet the inclusion criteria for the trial anymore, though it would depend on the study.” Or, the participant could take a drug or other product as a preventive prophylaxis, which could affect study participation. An example of this would be the misinformation around hydroxychloroquine.
“It is really important to keep in mind that the point of trials is to determine whether a new vaccine confers a benefit of protection and to build a profile of its side effects, if any,” says Alex John London, PhD, director of the Center for Ethics and Policy at Carnegie Mellon University in Pittsburgh. “Safety data is particularly important in the case of a vaccine since vaccines are delivered to ‘healthy’ people. I put [healthy] in quotes since although these people aren’t sick with the disease in question, they may have a wide range of underlying medical conditions. One of the things we want to find out is whether there are people with particular medical conditions that experience more severe side effects than others.”
If participants seek the vaccine on their own outside the trial, that can have important consequences for their own health and for the integrity of the study. “While they are blinded, participants don’t necessarily know which intervention they received. If they received the vaccine, then getting vaccinated again would consume a scarce resource unnecessarily and expose the person to unknown risks of taking two vaccines,” London says.
Part of the point of the two arms is to compare the rate of various problems in those who received the investigational vaccine and those who did not, London says. “If trial participants seek the vaccine on their own, it detracts from the trial’s ability to estimate how many adverse events would have happened anyway and how many might be due to the vaccine.”
Informing About Adverse Effects
Experiences with high fevers and other adverse effects in vaccine trials also are hitting the national media. One nurse who said she worked in research wrote an account in the Journal of the American Medical Association about experiencing a 104.9°F fever after receiving a second injection in a trial.4 In addition to the fever, she felt light-headed, chilled, nauseous, and had a “splitting” headache. “The adverse effects of the vaccine — even if, at worst, they all happen at once — are transient and a normal sign of reactogenicity, signaling an effective immune response,” she wrote. However, the author said that despite the “extensive information she had on the research process and vaccine,” she was unprepared. “[O]n a personal level, I did not get the message that I should anticipate a reactogenic response.” She is concerned that other patients will not get the message that adverse effects with the vaccine show that the vaccine is working.
“In the context of potential adverse events, I would imagine that is sufficiently covered in the IC [informed consent], though I think there are more proactive means of administering IC in the context of a public health emergency, such as providing additional information about possible vaccine misinformation or how to respond to potential media reports about a vaccines’ safety profile — perhaps reiterating the role of the [The Data and Safety Monitoring Board] and IRB for patient safety, that need to be given more attention,” Mackey says. “I also think that there could be special protocols for more dynamic consent management and reconsent, not just as a trial progresses and more data become available, but ultimately as the pandemic progresses and conditions change on the ground — risk of infection, number of cases, availability of other treatments, etc.”
One of the challenges of IC is to communicate the relevant uncertainties to participants in terms they will understand, London says. “It is very important that we do not foster the ‘therapeutic misconception,’ which is the perception that study participation entails access to validated medical treatment. In the case of novel mRNA [messenger RNA] vaccines, I think it is also important to make sure that participants understand that the reason the trial is slated to last for two years is because it is important that we have a clear picture of the safety of the vaccine in a large and diverse population.”
However, even in the best case, it would not be surprising if the participants did not remember all the information given to them during the consent process. “It’s also difficult to anticipate at the start of the trial when results will be available since a lot depends on where the studies are carried out and the transmission rates in those places,” London says.
If the public health response had been better, the estimates of efficacy might be delayed. “As it is, because COVID-19 is basically out of control at the moment, they’re able to see enough cases to estimate efficacy fairly quickly,” London adds. “Now we find ourselves in a position in which we have very promising estimates of efficacy fairly early on in the anticipated life of the trial.”
Study participants certainly have a right to be updated on the new information that has come from the trial they are in and all study participants are free to withdraw at any time. “I think they should be encouraged to remain in the trial because of the importance of generating a clear picture of the side effect profile of a novel vaccine, using a novel strategy, “ London says. “If it is permissible to ask the public to wait while early doses are provided to healthcare workers or people at elevated risk, then I think it is permissible to ask study participants to remain in the trial. It is never permissible to force people to remain in a trial.”
- WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine Evaluation; Krause PR, Fleming TR, Longini IM, et al. Placebo-controlled trials of COVID-19 vaccines — Why we still need them. N Engl J Med 2020; Dec. 2. doi:10.1056/NEJMp2033538.
- Zimmer C, Weiland N. Many Trial Volunteers Got Placebo Vaccines. Do they New Deserve the Real Ones? The New York Times. Dec. 2, 2020. https://nyti.ms/2WfUs86
- Regulations.gov. Comment from Pfizer Inc. Oct. 16, 2020. Comment ID: FDA-2020-N-1898-0018. https://bit.ly/3agMXWW
- Choi KR. A nursing researcher’s experience in a COVID-19 vaccine trial. JAMA Intern Med 2020; Dec 7. doi:10.1001/jamainternmed.2020.7087.