COVID-19 Vaccine Developers Adjust Phase 3 Trial Protocols to Allow Authorized Vaccines

COVID-19 vaccine developers are faced with an ethical quandary — whether to let phase 3 trial participants become “unblinded” and to receive authorized vaccines as they become available, which could hinder the collection of meaningful trial data.

Pfizer, which has received emergency approvals in the U.S. Canada and the UK, says the company has “an ethical duty to create a pathway within [its] study for interested, eligible participants in the placebo group to have access to the vaccine as regulatory authorities make decisions about authorization or approval of the vaccine candidate around the world.”

Pfizer has prepared a trial protocol amendment, pending input from regulators, that is “designed so that interested and eligible participants in the placebo group would have the option to receive the vaccine at scheduled timepoints in the study,” a company spokesperson told FDAnews, adding that any move from the placebo group to the vaccine group “would be completely optional, and participants would be encouraged to remain blinded throughout the full study duration.”

Moderna appears to be taking a similar tack. At yesterday’s meeting of the FDA’s vaccines advisory committee that recommended Emergency Use Authorization for Moderna’s COVID-19 vaccine, FDA Medical Officer Rachel Zhang said the agency is still in discussions with the company about revisions to its phase 3 trial in the event an EUA is given, but that the drugmaker is generally proposing to make no changes for participants who want to remain blinded.

Zhang said Moderna plans to “re-consent” participants who decide to be unblinded and to offer the vaccine to patients in the placebo group. Regardless of their decisions or which treatment they receive, all participants will be monitored for two years.

Much of the FDA advisory panel’s discussion surrounded Moderna’s plans to offer placebo patients in its phase 3 trial the option to receive its mRNA-1273 vaccine should it earn EUA. Some committee members worried that doing so could jeopardize the integrity of the trial’s data and argued that the study should continue blinded for a time.

“You could use the vaccine that [is] coming to expiration but you do it in a blinded manner and in that way, you uphold the integrity [of the trial] and the ability to really look forward. It’s going to change everyone’s behavior otherwise,” suggested Hayley Gans, a pediatrics and infectious diseases expert at Stanford University Medical Center. “The only way I see that we can really hold on to the integrity and continue learning something is to continue the blinding of the study.”

Sheldon Toubman, a staff attorney with the New Haven Legal Assistance Association, said he “is very concerned about Moderna’s proposal” to unblind its placebo group. “If they’re going to unblind, they should do it on the basis of when a group comes up in its priority and not unblind everyone right away, which is what Moderna has proposed.”

On the other hand, James Hildreth, president and CEO of Meharry Medical College, said it could be unethical not to offer the vaccine to the placebo group after authorization and worried that the trial might risk losing participants. “I just really feel strongly, if we don’t do that, we’re going to lose the placebo participants and maybe do harm for future recruitment of vaccine trials,” he said, suggesting an open-label crossover study as the best way forward.

Mark Sawyer, an infectious disease specialist at Rady Children’s Hospital, also voiced support for an open-label crossover approach, contending that the trial’s blind has already been impacted by common vaccine side effects. “People are really going to figure out whether they got vaccine or placebo. If you got two injections and each time your arm hurt and you got malaise the next day, you’re going to figure out that you got the vaccine. I think behaviors are going to be modified based on that, so my opinion is that blind is already eroded to the point where it probably won’t matter.”

Unblinding isn’t a universally accepted option for balancing the need for additional vaccine data with the desire to protect high-risk participants against infection. At Thursday’s vaccine advisory committee meeting, Stanford University’s Steven Goodman argued in favor of a crossover trial design. This would mean volunteers who already received a vaccine would be given a placebo and vice versa, allowing companies to evaluate their product’s safety and long-term efficacy.

This idea has gained some support, including from Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. But some sponsors, including Pfizer, are unsure if such a trial protocol change this late in the game would be workable.

Pfizer and BioNTech recently announced that they are offering their vaccine, BNT162b2, to eligible trial participants while keeping them enrolled, raising concerns about data integrity, though it will be done in a controlled manner. Currently, healthcare personnel and long-term care facility residents participating in their trial are the only ones who can opt to receive the vaccine. For those who aren’t yet eligible, study doctors will discuss the vaccine transition option with them approximately six months after their second injections, the companies said.

AstraZeneca (AZ) may have more to lose if it allows unblinding, given the delays in the trials of the company’s vaccine and the ongoing controversy over a reported dosing error that accidentally led to improved efficacy results (DID, Dec. 17).

As other vaccines receive EUAs or full approval, and participants in the AZD1222 trial are eligible to receive them, “it is our ethical responsibility to give trial volunteers options for their participation,” an AZ spokesperson told FDAnews. And the company has provided guidance to trial investigators who will be responsible for overseeing the unblinding process. ― Jason Scott and James Miessler