As the world looks for a safe and effective vaccine against SARS-CoV-2, IRBs should review the bioethical implications of this type of study design, including assessing risks and benefits.

Several research ethicists offer these suggestions:

• Ensure the purpose of the trial is clear. “There needs to be a tight case that benefits to society are sufficient to redeem the considerable risks and uncertainties,” says Jonathan Kimmelman, PhD, James McGill professor and director of the biomedical ethics unit at McGill University in Montreal. “One particular thing IRBs should think about is whether findings for the study are likely to actually inform vaccine development. IRBs should think of any trial as a diagnostic; they are done to inform a decision of whether to abandon a vaccine or develop it further, and whether to use a vaccine in practice.”

The trial should not be conducted unless it is going to inform an important decision. “IRB members might be surprised to discover that a lot of trials are done without a clear path toward making a decision,” Kimmelman says. “For example, drug companies might cut short a development program — not because the treatment they are testing flags, but because of a shift in commercial priorities.”

These sort of abortive research decisions disrespect patients and volunteers, who do not consider themselves as useful only to help companies make strategic decisions, he adds.

• Create a concrete plan. “Before [a challenge] study could be launched, there should be a concrete plan, outlining the many steps in development for the vaccine candidate in question, and an apples-to-apples comparison with alternative strategies, including adaptive trials that will compress development timelines,” says Alex John London, PhD, Clara L. West professor of ethics and philosophy and director of the Center for Ethics and Policy at Carnegie Mellon University.

“These plans should take into account the extra steps that are needed to mount a challenge study, including the creation of a challenge strain and the determination of the challenge dose, as well as side-by-side plans for assessing the safety of the vaccine candidate in the diverse populations to which it is likely to be administered,” London says.

• Assess the study’s ethical precautions and safety steps. “Owing to the novelty, technicality, and stakes [of a SARS-CoV-2 vaccine], my view is you need a central and specialized IRB to approve the first few infection challenge trials,” Kimmelman says.

With a few exceptions, there is not a good record of using specialized review mechanisms, he notes. A recent journal article outlines these mechanisms.1

A challenge study should only go forward if there is an acceptable plan to manage risks. But developing a risk management plan is not a sufficient reason to take this approach, London says.

“To warrant taking this approach in the first place, there must be a credible plan to ensure both social value and to secure trust in the results of the larger plan of development of which that study is a part,” London adds.

• Determine whether the sponsor can produce a successful vaccine. Kimmelman says research organizations and IRBs should ask these questions:

- Is the sponsor set up to follow up an infection challenge study with a field study?

- Are they set up to manufacture a vaccine if it shows promise in challenge and field studies?

- Are their commercial partners set up this way?

- Is the commercial partner committed to following up results?

“If the answers to these questions are tentative, IRBs should look askance at the proposal,” Kimmelman says.

• Ensure transparency. “How committed is the sponsor to disseminate findings promptly so that others can learn about how COVID-19 behaves in healthy humans?” Kimmelman asks. “Will they publish negative or inconclusive findings promptly so we can reduce some of the uncertainty surrounding COVID-19?”

IRBs should check for publication plans, press for data-sharing, and ask about the deposition of individual patient data in a learned intermediary database, Kimmelman adds.

REFERENCE

  1. Sha SK, Miller FG, Darton TC, et al. Ethics of controlled human infection to address COVID-19. Science 2020;368:832-834.