Information regarding COVID-19 has rapidly evolved. The content in this article provides a historical snapshot of events surrounding the date of posting.

As scientists race to learn more about COVID-19 and how to treat and prevent it, there are many difficult ethical questions being debated in the research community. 

For instance, is it safe to perform COVID-19 vaccine challenge trials—where people are given a vaccine candidate and then intentionally exposed to the virus—since there are currently no known cures for the coronavirus? Many worry that the risks to participants might outweigh the benefits. 

There are also important ethical issues around the logistics of placebo controlled trials involving COVID-19 vaccine candidates. Initially, most of the current studies were designed to span a few years to follow the efficacy of the vaccines over the long term, and people in the control groups were promised they would receive the vaccine at the end of the study period once one became available. However, now that three vaccines have already received emergency approval by the U.S. Food and Drug Administration (FDA) and others are in the wings, controversy revolves around whether the studies should be formally stopped and vaccines given to those who received the placebo during the study. 

The Importance of Performing Safe Clinical Trials 

While clinical trials using human subjects can pose real risks for participants, they can also bring important benefits, not only to those taking part in the effort but also for larger populations who may be served by the developments. In order to manage the risk/benefit ratio in the best way, researchers need to understand the risks and potential benefits involved and determine how to balance them effectively, according to Susan Kornetsky, MPH, director of clinical research compliance at Boston Children’s Hospital. Kornetsky also shares her expertise in medical ethics as a member of the faculty of Harvard Medical School’s Global Clinical Scholars Research Training program.  

“When we look at human subject clinical trials, the most important considerations are first whether the risks outweigh the benefits and then how to assure a meaningful informed consent process so that subjects understand what is involved, the risks, the benefits and the alternatives. Then they can make an educated and voluntary choice whether to participate,” she says.  

Kornetsky also points out that while COVID-19 is a relatively new disease, there have long been serious ethical questions around human subject clinical trials for a host of drugs, devices and behavioral therapies to treat various other conditions. There is also a universal imperative that researchers conducting any studies involving human subjects go to great lengths to ensure fairness and safety for all involved.  

“The ethical principles of autonomy, beneficence and justice, which drive current clinical trial regulations, are the same no matter where in the world you are located,” she says.  

To ensure these principles are properly considered, she points out that most research proposals need to be approved and monitored by an Independent Review Board (IRB), which is a multi-disciplinary ethics committee typically consisting of health care professionals as well as non-health care members. IRBs often also include the voice of the subjects who will participate. 

“The ethics committee I run at Boston Children’s includes four external members, in addition to our medical experts, and these members bring up points from the perspective of the patients,” Kornetsky says. This can provide very valuable insights. 

The Evolving Role of Clinical Trials 

To fully understand the role of the IRB, Kornetsky points out that it’s important to view it in the context of the clinical trial field and its history. In fact, many of the current rules and regulations governing research efforts have evolved because of past abuses of vulnerable populations, including prisoners and those who are institutionalized.  

“In the U.S, in the past, children institutionalized with behavioral health diagnoses were used for research, and this led to the current additional protections for pediatric research,” she says. Just a few decades ago, people viewed participating in a clinical trial unfavorably and often with a great deal of mistrust. “But then the AIDS/HIV epidemic in the 80s changed all that. We didn’t know how to treat this disease; this led us to view research studies as a real benefit, since they had the potential to provide participants with access to a drug or treatment that might make a difference,” she recalls. Since then, clinical trials have become much more accepted among the general population and many have the desire to participate; however, there still are some populations that distrust the research enterprise.   

Key Points to Guide Human Subject Clinical Trials 

“Today, we know we need to protect people, as well as offer expanded access to drugs even while in clinical trial, since they could potentially save lives,” Kornetsky stresses. To this end, there are some key areas within the very complex medical landscape that researchers should consider when designing clinical trials—and that ethics boards should also consider when reviewing the plans for each research effort. 

1. Define the risk

It may be a physical risk, a legal risk or a psychological risk. “What you want to focus on is really the probability of such harm occurring as a result of participating in research. Keep in mind it’s the chance of harm you are capturing, rather than the actual harm itself,” Kornetsky stresses. When you think about potential risk, you should also consider how severe it could be and how many people could be affected, and use existing procedures to reduce the likelihood that harm will occur. “If you are worried someone might have an allergic reaction to a drug, you can give them an antihistamine beforehand to minimize risk and also administer the drug in a medical setting where you can be prepared to respond if an anaphylactic reaction occurs,” she says.

2. Select qualified participants

This requires making sure you have good eligibility criteria to select who should participate in the trial. In practical terms, this means pulling together a group that represents the population and also includes the people most in need for such an intervention (such as older adults to test the efficacy of the COVID-19 vaccine), but at the same time, you need to be managing their risk (such as getting COVID-19 or having an adverse reaction).  

3. Evaluate the potential for benefit

You need to understand the desired outcome that you hope to achieve or the research question you need to answer, and why this is important. “We also define the probability that this outcome may happen and look at how great the benefit is that it brings. Not all research will benefit an individual but it could benefit others in the future.” 

4. Minimize the risk

“Studies must follow sound research design and not expose subjects to unnecessary risks,” Kornetsky says. This means that whenever possible, researchers should manage risks to subjects by coordinating with existing medical care. 

“If the study requires a certain type of biopsy that requires sedation, is there any other time the patient is being sedated for another purpose so you could do the biopsy then? Or in children, if you need a blood draw, could you do it at the same time as when you draw blood for a clinical type of test?” she asks. 

5. Provide a meaningful informed consent process

Everyone who takes part in a clinical trial must receive an informed consent form that explains all aspects of the study including the potential risks and benefits. Participation in research is always voluntary. Participants must also have the chance to ask questions, understand alternative options and be able to withdraw at any time during the clinical trial process.

6. Protect vulnerable subjects

This includes children, pregnant women and their unborn babies, decisionally impaired individuals, people who are handicapped, prisoners and those who are educationally and socially disadvantaged. Researchers need to think about their goals for wanting to use these populations and to determine if they can answer the same research question without using any vulnerable subjects. 

7. Ensure transparency

It’s important to have a plan to share any adverse outcomes or complications that may arise. In addition, as the clinical trial process progresses, if any changes are made to the actual design, such as adding a test, this alteration must be submitted to the IRB for approval again. In some cases, participants may be asked to consent with updated information  This helps ensure everyone is on the same page every step of the way. 

Consider the Big Picture in Medical Research 

While there are so many ethical issues to consider when designing and implementing clinical trials, a well-run effort that takes into account all of these important principles has the potential to greatly benefit large groups of people. And as has been demonstrated by the approval of two COVID-19 vaccines currently being administered around the nation and abroad, despite the controversy that exists, the results of clinical trials like these can ultimately make a significant difference for the population at large, as well as even for the broader good of humanity.  

Written by Lisa D. Ellis